- Email: [email protected]
Epidemiological study on extrapyramidal side effects with neuroleptics
P.3 Psychotic disorders and antipsychotics O'CallaghanE., GibsonT., Colohan H.A. et al.: Seasonof birth in schizophrenia. Evidence for confinement of an excess of winter births to patients without a familyhistory of mentaldisorder. Br. J. Psychiatry, 1911a, 158, 764-769. Pallast E.G.M., Jongbloet P.h., Straatman H.M., Zielhuis G.A.: Ecess seasonality of births amongpatientswith schizophrenia and seasonal ovopathy. Schizophr. Bull., 1994,20,269-276. Sham P.e., O'Callaghan E., Takei N. en al.: Schizophrenia following prenatal exposure to influenza epidemics between 1939 and 1960. Br. J. Psychiatry, 1992, 160, 461-466. Takei N., Sham P., O'CallaghanE. et al.: Prenatal exposure to influenza and thedevelopment of schizophrenia: Is theeffect confined to females? Am.1. Psychiatry, 1994,151,177-119.
IP.3.028I Epidemiological study on extrapyramidal side effects withneuroleptics
D. Berardi, A. Giannelli, R. Biscione, M. Dell'Ani, G. Ferrari. Institute of Psychiatry of Bologna University, viale C. Pepoli, 5, 40123Bologna, Italy The appearance of EPS during neuroleptic (NL) treatment may have important clinical consequences: the EPS can cause treatment intolerance and in somecases non-complianceand also seemsrelated to a more severe psychopathological state. Akathisia can in fact bring on an accentuation of anxiousness, tension, irritability, impulsiveness and violent behaviour, both self and heterodirected; pseudoparkinson can be associated with akinesia, emotional withdrawal, and blunted affect. The Institute of Psychiatry of Bologna University, with the collaboration of 7 Community Mental Health Centres (CMHC), conducted an epidemiological study to evaluate the prevalence of akathisia and pseudoparkinson and their psychic effects in 140 of out-patients undergoing !,;'L treatment. The patients were evaluated using: Brief Psychiatric Rating Scale (BPRS), Clinical Global Instrument(CGI); Simpson Angus Extrapyramidal Rating Scale (EPRS); Barnes Akathisia Rating Scale (BARS); modified Leeds Anxiety Scale (mLAS); Van Putten Scale for Subjective Dysphoria. Akathisia was present in 27.1% of patients and psedoparkinson in 22.1%. The 2 EPS were closely associated, as akathisia was present in 2/3 of patients with pseudoparkinson(p < 0.00(1). The NL's were given, on the average, in low doses. This not withstanding, patients with EPS received significantly higher dosages in respect to patients without EPS: 306 versus 211 mg eq CPZ for akathisia and 322 versus 213 mg for pseudoparkinson. The patients with EPS resulted as much more serious than those without EPS on the CGI scale and had significantly higher BPRS global scores (p < O.OOOl) (respectively 45.7 vs 37.6 for akathisia and 47 vs 37.7 for pseudoparkinson). They had higher scores on these items: conceptual disorganisation, tension, mannerisms, excitement, emotional withdrawal, suspiciousness. motor retardation, uncooperativeness, blunted affect, and disorientation. A two-way ANOVAshowed that the high scoreon the item "excitement" was directly related to the presence of akathisia, whereas remaining items were correlated to the presence of pseudoparkinson either alone or in association with akathisia. To explain the association between EPS and a more severe psychopathological state it is possible to hypothesise that patients, more serious psychopathologically, had a higher risk of developing EPS as they were exposed to higher doses of NL's. However, our hypothesis is that akathisia and pseudoparkinson can play a role in the worsening of psychiatric symptoms. It was seen that on all dosage levels, patients with akathisia showed a much higher total BPRS score in respect to patients without side effects. A regression logistic analysis was then conducted considering akathisia as a dependent variable, and considering BPRS. the diagnostic groups, the mean neuroleptic dosage, and pseudoparkinson as covariates. This analysis showed a strict correlation between the seriousness on the BPRS scale (p < 0.05) and the presence of pseudoparkinson (p < 0.000I) on one end and akathisia on the other. This data would support the hypothesis that akathisia is correlated to a high severity measured directly on the BPRS scale, independently from the dosage. Since the results of our research were derived from data obtained during clinical observation, their suggestiveness would benefit from experimental confirmation.
S4-l1l
References [I] Van Purten, T., May, P.RA (1978) Akinetic depression in schizophrenia Arch. Gen. Psychiatry, 35, I 10t. [2] Halstead,S. M., Barnes, T.R.E., Speller, J.e. (1994) Akathisia: Prevalence and associated dysphoria in an in-patient population with chronic schizophrenia. Br. 1. Psychiatry, 164, 177-183.
I P.3.029I Thesafety profile of amlsulpride, an "atypical" antipsychotic C. Favennec, W. Rein, S. Turjanski. Synthelabo Recherche. 92225 Bagneux; Synthelabo, 92350 Plessis-Robinson (France) Amisulpride (AMI), a substituted benzamide, is an "atypical" antipsychotic with a selective high affinity for the dopamineD2 and D3receptors. High recommended doses (400 to 800 mg/d; 800 to 1200 mg/d have been used in some patients) are effective in productive schizophrenia probably via the decrease of dopaminergic transmission by postsynaptic receptor blockade. Low doses (50 to 300 mg/d) are effective in schizophrenic patients with deficit or primary negative symptoms probably via the increase of dopaminergictransmission by presynaptic receptor blockade. The safety profile of AMI based on the results of 5 short-term and 4 long-term studies will be presented. Overall, 1170patients were evaluated 749 of whom were treated with AMI, 240 with haloperidol (H), 62 with flupentixol and 119 received placebo. 838 (72%) patients were included in studies in productive schizophrenia and 332 (28%) patients in studies in deficitschizophrenia. 104patients received AMI for at least II months. Clinical safety data were collected by either spontaneous reporting and/or adverse event scales. Adverse reactions associated to antipsychotics may be classified in two categories: J. Some are frequent and not related to an individual hypersensitivity: - Psychic disorders: usually mild and well tolerated. - Increased hyperprolactinaemia: with clinical consequences particularly in women. Informing patients on their occurrence and reversibility make them usually acceptable. - Early extrapyramidal symptoms: they are improved by antiparkinsonian drugs, and reversible with discontinuation of antipsychotics. However their incidence (> 50% with some antipsychotics), the functional and psychological consequences make them a crucial argument for choice between antipsychotics. Decrease of their incidence is one of the criteria of identification of"atypical antipsychotics", 2. Uncommon reactions usually more severe: seizures, in at-risk patients; tardive dyskinesia. malignant syndrome, immediately Iifethreatening; sudden death and/or life-threatening cardiac disorders; less specific: agranulocytosis and liver disorders. In summary, safety evaluation of an antipsychotic is based on the incidence of early extrapyramidal symptoms and on the occurrence of the serious or fatal reactions. Based on the above-mentioned studies, the safety profileof arnisulpride may be summarizedas follows: I. Incidence of early extrapyramidal syndromes: In productive schizophrenia, they are less frequent with AMI (39%) at doses up to 800 mgld than with H (58%) (UKU scale). In schizophrenia with negative symptoms, difference is much more important: 12% for AMI at doses up to 300 mgld vs 52% for H (open report), and amisulpride is as well tolerated as placebo except for hyperprolactinaemia (6.6%). 2. Occurrence of serious or fatalllife-threatening reactions: Seizures were not more frequent with amisulpride (2f749) than with placebo (3/119). Incidence of tardive dyskinesia with amisulpride was 4/749. No case of malignant syndrome, sudden death, cardiac disorders, agranulocytosis or hepatitis was recorded during the studies. The clinical data from studies show that amisulpride can be safely used in schizophrenic patients with predominant positive symptoms as well as in schizophrenic patients with deficit symptoms.
IP.3.028I Epidemiological study on extrapyramidal side effects withneuroleptics
D. Berardi, A. Giannelli, R. Biscione, M. Dell'Ani, G. Ferrari. Institute of Psychiatry of Bologna University, viale C. Pepoli, 5, 40123Bologna, Italy The appearance of EPS during neuroleptic (NL) treatment may have important clinical consequences: the EPS can cause treatment intolerance and in somecases non-complianceand also seemsrelated to a more severe psychopathological state. Akathisia can in fact bring on an accentuation of anxiousness, tension, irritability, impulsiveness and violent behaviour, both self and heterodirected; pseudoparkinson can be associated with akinesia, emotional withdrawal, and blunted affect. The Institute of Psychiatry of Bologna University, with the collaboration of 7 Community Mental Health Centres (CMHC), conducted an epidemiological study to evaluate the prevalence of akathisia and pseudoparkinson and their psychic effects in 140 of out-patients undergoing !,;'L treatment. The patients were evaluated using: Brief Psychiatric Rating Scale (BPRS), Clinical Global Instrument(CGI); Simpson Angus Extrapyramidal Rating Scale (EPRS); Barnes Akathisia Rating Scale (BARS); modified Leeds Anxiety Scale (mLAS); Van Putten Scale for Subjective Dysphoria. Akathisia was present in 27.1% of patients and psedoparkinson in 22.1%. The 2 EPS were closely associated, as akathisia was present in 2/3 of patients with pseudoparkinson(p < 0.00(1). The NL's were given, on the average, in low doses. This not withstanding, patients with EPS received significantly higher dosages in respect to patients without EPS: 306 versus 211 mg eq CPZ for akathisia and 322 versus 213 mg for pseudoparkinson. The patients with EPS resulted as much more serious than those without EPS on the CGI scale and had significantly higher BPRS global scores (p < O.OOOl) (respectively 45.7 vs 37.6 for akathisia and 47 vs 37.7 for pseudoparkinson). They had higher scores on these items: conceptual disorganisation, tension, mannerisms, excitement, emotional withdrawal, suspiciousness. motor retardation, uncooperativeness, blunted affect, and disorientation. A two-way ANOVAshowed that the high scoreon the item "excitement" was directly related to the presence of akathisia, whereas remaining items were correlated to the presence of pseudoparkinson either alone or in association with akathisia. To explain the association between EPS and a more severe psychopathological state it is possible to hypothesise that patients, more serious psychopathologically, had a higher risk of developing EPS as they were exposed to higher doses of NL's. However, our hypothesis is that akathisia and pseudoparkinson can play a role in the worsening of psychiatric symptoms. It was seen that on all dosage levels, patients with akathisia showed a much higher total BPRS score in respect to patients without side effects. A regression logistic analysis was then conducted considering akathisia as a dependent variable, and considering BPRS. the diagnostic groups, the mean neuroleptic dosage, and pseudoparkinson as covariates. This analysis showed a strict correlation between the seriousness on the BPRS scale (p < 0.05) and the presence of pseudoparkinson (p < 0.000I) on one end and akathisia on the other. This data would support the hypothesis that akathisia is correlated to a high severity measured directly on the BPRS scale, independently from the dosage. Since the results of our research were derived from data obtained during clinical observation, their suggestiveness would benefit from experimental confirmation.
S4-l1l
References [I] Van Purten, T., May, P.RA (1978) Akinetic depression in schizophrenia Arch. Gen. Psychiatry, 35, I 10t. [2] Halstead,S. M., Barnes, T.R.E., Speller, J.e. (1994) Akathisia: Prevalence and associated dysphoria in an in-patient population with chronic schizophrenia. Br. 1. Psychiatry, 164, 177-183.
I P.3.029I Thesafety profile of amlsulpride, an "atypical" antipsychotic C. Favennec, W. Rein, S. Turjanski. Synthelabo Recherche. 92225 Bagneux; Synthelabo, 92350 Plessis-Robinson (France) Amisulpride (AMI), a substituted benzamide, is an "atypical" antipsychotic with a selective high affinity for the dopamineD2 and D3receptors. High recommended doses (400 to 800 mg/d; 800 to 1200 mg/d have been used in some patients) are effective in productive schizophrenia probably via the decrease of dopaminergic transmission by postsynaptic receptor blockade. Low doses (50 to 300 mg/d) are effective in schizophrenic patients with deficit or primary negative symptoms probably via the increase of dopaminergictransmission by presynaptic receptor blockade. The safety profile of AMI based on the results of 5 short-term and 4 long-term studies will be presented. Overall, 1170patients were evaluated 749 of whom were treated with AMI, 240 with haloperidol (H), 62 with flupentixol and 119 received placebo. 838 (72%) patients were included in studies in productive schizophrenia and 332 (28%) patients in studies in deficitschizophrenia. 104patients received AMI for at least II months. Clinical safety data were collected by either spontaneous reporting and/or adverse event scales. Adverse reactions associated to antipsychotics may be classified in two categories: J. Some are frequent and not related to an individual hypersensitivity: - Psychic disorders: usually mild and well tolerated. - Increased hyperprolactinaemia: with clinical consequences particularly in women. Informing patients on their occurrence and reversibility make them usually acceptable. - Early extrapyramidal symptoms: they are improved by antiparkinsonian drugs, and reversible with discontinuation of antipsychotics. However their incidence (> 50% with some antipsychotics), the functional and psychological consequences make them a crucial argument for choice between antipsychotics. Decrease of their incidence is one of the criteria of identification of"atypical antipsychotics", 2. Uncommon reactions usually more severe: seizures, in at-risk patients; tardive dyskinesia. malignant syndrome, immediately Iifethreatening; sudden death and/or life-threatening cardiac disorders; less specific: agranulocytosis and liver disorders. In summary, safety evaluation of an antipsychotic is based on the incidence of early extrapyramidal symptoms and on the occurrence of the serious or fatal reactions. Based on the above-mentioned studies, the safety profileof arnisulpride may be summarizedas follows: I. Incidence of early extrapyramidal syndromes: In productive schizophrenia, they are less frequent with AMI (39%) at doses up to 800 mgld than with H (58%) (UKU scale). In schizophrenia with negative symptoms, difference is much more important: 12% for AMI at doses up to 300 mgld vs 52% for H (open report), and amisulpride is as well tolerated as placebo except for hyperprolactinaemia (6.6%). 2. Occurrence of serious or fatalllife-threatening reactions: Seizures were not more frequent with amisulpride (2f749) than with placebo (3/119). Incidence of tardive dyskinesia with amisulpride was 4/749. No case of malignant syndrome, sudden death, cardiac disorders, agranulocytosis or hepatitis was recorded during the studies. The clinical data from studies show that amisulpride can be safely used in schizophrenic patients with predominant positive symptoms as well as in schizophrenic patients with deficit symptoms.