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rG-CSF treatment of clozapine-induced agranulocytosis
SATURDAY, MAY 21
identified. The average dose was 300 mg/d. This study supports the f'mdings in the adult population of the anti-aggressive effect of clozapine. In this sample, there was a high comorbidity of psychosis with other disorders such as Tourette's Disorder, Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder. The sample as a whole, had numerous pharmacological failures. Blood cell counts remained stable. In four patients, when clozapine was discontinued, symptomatology reemerged including the aggression, in only one patient, clozapine was discontinued because of side effects that were not hematological in nature. The most common side effects were salivation and weight gain. This study supports previous findings of the anti-aggressive effects of clozapine. Clozapine's affinity for the 5-HT2 receptors might explain this effect.
470. EFFECTS OF ALPRAZOLAM ON COGNITIVE FUNCTION OF SCHIZOPHRENICS A.L. Hoff l, M. Costa I, D. Harris l, J. Stern 2, F. Manfredi 2, T. Chart2, N. Turetsky2, S. Espinoza l, N. Riley 2, V. Reu#, & O.M. Wolkowitz 2 tBiologicai Psychiatry Treatment and Research Center, Napa State Hospital, Napa, CA; 2Department of Psychiatry, UCSF, San Francisco, CA Previous studies have suggested that alprazolam may have therapeutic efficacy in some schizophrenic patients when given adjunctively with traditional neuroleptic regimens (Wolkowitz et al., i 988). The mechanisms of this action, however, are unknown, in a pilot study, patients with radiographic evidence of prefrontal cortical 0PFC) atrophy showed a better antipsychotie response to alWazolam augmentation (Ibid.). Recent theories of cortico-limbic dysregulation in schizophrenia and studies showing increased subcortical DA responsivity to stress in PFC-lesioned animals, prompted us to examine PFC function in alprazolam treated patients. We performed neuropsychological testing (Wisconsin Card Sort and California Verbal Learning Tes0 before and after 4 weeks of adjunctive alprazolam (n=lT) or placebo (n-19) administration. RDC chronic schizophrenic patients from Napa State Hospital (n-i 5)and Langley Porter Psychiatric Institute (n-21) were tested. GROUP (Alprazolam, Placebo) by SITE (Napa, LPPI) repeated measures ANOVA's (TIME as repeated measure) were conducted. Statistically significantGROUP X TIME interactions were found, suggesting that alprazolam patients made fewer perseverative responses and errors than placebo patients, but were more likely to fail in maintaining cognitive set, possibly related to a reduction in memory functions. Analysis of CVLT data indicated that the alprazolam group had a reduction in long-term memory not seen in the placebo group. Anterograde memory deficits are well recognized benzodiazepine side effects (Wolkowitz et al., 1987); however, enhancement of PFC function is a novel observation. The present results suggest that perseverative responding on the WCST may be improved by alprazolam augmentation, which may have implications for understanding its effect in reducing psychotic symptoms and in stabilizing possible cortico-limbic dysregulafion.
471. WITHDRAWN 472. rG-CSF TREATMENT OF CLOZAPINEINDUCED AGRANULOCYTOSIS J.S. Lamberti, I'. Bellnier, J. Veneron, K. Patil, & S.B. Schwarzkopf Department of Psychiatry, University of Rochester Medical
BIOLPSYCHIATRY 745 1994;35:615-747
Center, 601 Eimwood Avenue, Rochester NY 14642 Agranulocytosis is the most serious side effect of clozapine therapy, occurring in an estimated ! % of all treated cases. Despite blood monitoring there have been 256 cases of clozapine-induced agranulocytosis with 9 fatalities in the United States since 1990. Strategies are needed to manage clozapine-induced agranulocytosis more safely. Recombinant granulocyte colony-stimulating factor (rG-CSF) has been shown to reduce the incidence of infection in patients receiving myelosuppressive anti-cancer drugs, rG-CSF has also been reported successful in treating a number of patients with drug-induced agranulocytosis. Recently, Weide et al. (1992) and Gershon et al. (1992) have reported treating clozapine-induced agranulocytosis with rG-CSF. We present 2 patients with clozapine-induced agranulocytosis successfully treated with rG-CSF. A.C. is a 42 y/o man with chronic paranoid schizophrenia who developed biopsy-confirmed agranulocytosis after I I weeks of clozapine therapy. WBC and absolute neutrophil count (ANC) at the time of rO-CSF initiation were ! 100 and 0 respectively. Following 7 days of treatment with rG-CSF 300 I~g sq daily, WBC/ANC rebounded to 3400 and 1800 respectively. On day 8 of treatment, WBC/ANC were 6600 and 4300 respectively. A.M. is a 45 y/o man with chronic paranoid schizophrenia who developed biopsy-confirmed agranulocytosis following 7 weeks of clozapine. WBC/ANC at the time of rG-CSF initiation were 2000 and 60 respectively, rG.CSF was begun at 300 ug sq daily, and WBC/ANC rebounded to 4200/924 after 5 days, and to 5400/1500 after 6 days of treatment. Treatment with rG-CSF appears to reduce the duration of clozapine-induced agranulocytosis, and may decrease the incidence of serious infection in this disorder.
473. CLOZAPINE TREATMENT IN PATIENTS WITH CHRONIC SCHIZOPHRENIA: EFFICACY AND PREDICTORS OF RESPONSE T.P. Su, A. Breier, A.K. Malhotra, R.E. Litman, J.K. Hsiao, & D. Pickar National Institutes of Health, National Institute of Mental Health, Experimental Therapeutics The clinical profle of clozapine responsiveness has not been established. The purpose of this study was to c examine the efficacy and predictors of response of clozapine in chronic schizophrenic patients. Forty patients (age 31.4 :L,6.8years, male 27, female ! 3) who met neuroleptic treatment resistance or intolerance criteria participated in a double-blind, placebo controlled, crossover study that compared clozapine and fluphenazine. Clozapine significantlyreduced total BPRS symptom scores in comparison with fluphenazine and placebo (p<0.01). Further, significant decreases of BPRS subscale scores (thought disorder, paranoid suspiciousness, anxiety depression but not withdrawal retardation) was also observed in ciozapine than in fiuphenazine (p<0.01). Of the 40 patients, twenty (50%) met a priori responder criteria. Clozapine response was significantly correlated with !) greater increase of AIMS (r--0.325, p¢0.05) and decrease of Simpson-Angus Scale scores (r-0.375, p~.02) during placebo treatment in comparison with fiuphenazine, and 2) higher BPRS anxiety.depression during fiuphenazine treatment (r-0.548, p<0.001). Patients with history of suicidal attempts derived better clozapine responses, compared to those without suicidal history (X2=3.2% Idf, p=0.071 ). These data suggest that clozapine's effects on systems involved with extrapyramidal symptoms and affective symptomatology are related to its superior efficacy. The results of this study confirms the previous findings of clozapine superiority (Pickar 1992), and provided a profile for predictors to clozapine treatment.
identified. The average dose was 300 mg/d. This study supports the f'mdings in the adult population of the anti-aggressive effect of clozapine. In this sample, there was a high comorbidity of psychosis with other disorders such as Tourette's Disorder, Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder. The sample as a whole, had numerous pharmacological failures. Blood cell counts remained stable. In four patients, when clozapine was discontinued, symptomatology reemerged including the aggression, in only one patient, clozapine was discontinued because of side effects that were not hematological in nature. The most common side effects were salivation and weight gain. This study supports previous findings of the anti-aggressive effects of clozapine. Clozapine's affinity for the 5-HT2 receptors might explain this effect.
470. EFFECTS OF ALPRAZOLAM ON COGNITIVE FUNCTION OF SCHIZOPHRENICS A.L. Hoff l, M. Costa I, D. Harris l, J. Stern 2, F. Manfredi 2, T. Chart2, N. Turetsky2, S. Espinoza l, N. Riley 2, V. Reu#, & O.M. Wolkowitz 2 tBiologicai Psychiatry Treatment and Research Center, Napa State Hospital, Napa, CA; 2Department of Psychiatry, UCSF, San Francisco, CA Previous studies have suggested that alprazolam may have therapeutic efficacy in some schizophrenic patients when given adjunctively with traditional neuroleptic regimens (Wolkowitz et al., i 988). The mechanisms of this action, however, are unknown, in a pilot study, patients with radiographic evidence of prefrontal cortical 0PFC) atrophy showed a better antipsychotie response to alWazolam augmentation (Ibid.). Recent theories of cortico-limbic dysregulation in schizophrenia and studies showing increased subcortical DA responsivity to stress in PFC-lesioned animals, prompted us to examine PFC function in alprazolam treated patients. We performed neuropsychological testing (Wisconsin Card Sort and California Verbal Learning Tes0 before and after 4 weeks of adjunctive alprazolam (n=lT) or placebo (n-19) administration. RDC chronic schizophrenic patients from Napa State Hospital (n-i 5)and Langley Porter Psychiatric Institute (n-21) were tested. GROUP (Alprazolam, Placebo) by SITE (Napa, LPPI) repeated measures ANOVA's (TIME as repeated measure) were conducted. Statistically significantGROUP X TIME interactions were found, suggesting that alprazolam patients made fewer perseverative responses and errors than placebo patients, but were more likely to fail in maintaining cognitive set, possibly related to a reduction in memory functions. Analysis of CVLT data indicated that the alprazolam group had a reduction in long-term memory not seen in the placebo group. Anterograde memory deficits are well recognized benzodiazepine side effects (Wolkowitz et al., 1987); however, enhancement of PFC function is a novel observation. The present results suggest that perseverative responding on the WCST may be improved by alprazolam augmentation, which may have implications for understanding its effect in reducing psychotic symptoms and in stabilizing possible cortico-limbic dysregulafion.
471. WITHDRAWN 472. rG-CSF TREATMENT OF CLOZAPINEINDUCED AGRANULOCYTOSIS J.S. Lamberti, I'. Bellnier, J. Veneron, K. Patil, & S.B. Schwarzkopf Department of Psychiatry, University of Rochester Medical
BIOLPSYCHIATRY 745 1994;35:615-747
Center, 601 Eimwood Avenue, Rochester NY 14642 Agranulocytosis is the most serious side effect of clozapine therapy, occurring in an estimated ! % of all treated cases. Despite blood monitoring there have been 256 cases of clozapine-induced agranulocytosis with 9 fatalities in the United States since 1990. Strategies are needed to manage clozapine-induced agranulocytosis more safely. Recombinant granulocyte colony-stimulating factor (rG-CSF) has been shown to reduce the incidence of infection in patients receiving myelosuppressive anti-cancer drugs, rG-CSF has also been reported successful in treating a number of patients with drug-induced agranulocytosis. Recently, Weide et al. (1992) and Gershon et al. (1992) have reported treating clozapine-induced agranulocytosis with rG-CSF. We present 2 patients with clozapine-induced agranulocytosis successfully treated with rG-CSF. A.C. is a 42 y/o man with chronic paranoid schizophrenia who developed biopsy-confirmed agranulocytosis after I I weeks of clozapine therapy. WBC and absolute neutrophil count (ANC) at the time of rO-CSF initiation were ! 100 and 0 respectively. Following 7 days of treatment with rG-CSF 300 I~g sq daily, WBC/ANC rebounded to 3400 and 1800 respectively. On day 8 of treatment, WBC/ANC were 6600 and 4300 respectively. A.M. is a 45 y/o man with chronic paranoid schizophrenia who developed biopsy-confirmed agranulocytosis following 7 weeks of clozapine. WBC/ANC at the time of rG-CSF initiation were 2000 and 60 respectively, rG.CSF was begun at 300 ug sq daily, and WBC/ANC rebounded to 4200/924 after 5 days, and to 5400/1500 after 6 days of treatment. Treatment with rG-CSF appears to reduce the duration of clozapine-induced agranulocytosis, and may decrease the incidence of serious infection in this disorder.
473. CLOZAPINE TREATMENT IN PATIENTS WITH CHRONIC SCHIZOPHRENIA: EFFICACY AND PREDICTORS OF RESPONSE T.P. Su, A. Breier, A.K. Malhotra, R.E. Litman, J.K. Hsiao, & D. Pickar National Institutes of Health, National Institute of Mental Health, Experimental Therapeutics The clinical profle of clozapine responsiveness has not been established. The purpose of this study was to c examine the efficacy and predictors of response of clozapine in chronic schizophrenic patients. Forty patients (age 31.4 :L,6.8years, male 27, female ! 3) who met neuroleptic treatment resistance or intolerance criteria participated in a double-blind, placebo controlled, crossover study that compared clozapine and fluphenazine. Clozapine significantlyreduced total BPRS symptom scores in comparison with fluphenazine and placebo (p<0.01). Further, significant decreases of BPRS subscale scores (thought disorder, paranoid suspiciousness, anxiety depression but not withdrawal retardation) was also observed in ciozapine than in fiuphenazine (p<0.01). Of the 40 patients, twenty (50%) met a priori responder criteria. Clozapine response was significantly correlated with !) greater increase of AIMS (r--0.325, p¢0.05) and decrease of Simpson-Angus Scale scores (r-0.375, p~.02) during placebo treatment in comparison with fiuphenazine, and 2) higher BPRS anxiety.depression during fiuphenazine treatment (r-0.548, p<0.001). Patients with history of suicidal attempts derived better clozapine responses, compared to those without suicidal history (X2=3.2% Idf, p=0.071 ). These data suggest that clozapine's effects on systems involved with extrapyramidal symptoms and affective symptomatology are related to its superior efficacy. The results of this study confirms the previous findings of clozapine superiority (Pickar 1992), and provided a profile for predictors to clozapine treatment.