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haloperidol ratios in schizophrenic patients
BIOL PSYCHIATRY
62A
Schizophrenia
! 991 ;29:43A- 185A
42
COMPARATIVE ANALYSIS OF HALOPERIDOL AND REDUCED HALOPERIDOL PLASMA LEVELS IN DIFFERENT ETHNIC POPULATIONS Wen-Ho Chang, M.D., Michael W. Jann, Pharm.D., Francis Y.F., Lam, Pharm.D., Hai-Gwo Hwu, M.D., Teng-Yi Chen, M.D., ShihKu Lin, M.D., La,-ry Ereshefsky, Phann.D., Stephen R. Saldad, Pharm.D., Ann L. Richards, Pharrn.D., William M. Schulteis, M.D. Taipei Cir.; Psychiatric Center (T.Y.C., S.K.L.), National Faiwan University Hospital (H.G.H.), Taipei, Taiwan, ROC. Mercer University, Atlanta, GA (M.W,I.), The University of Texas, Austin (F.Y.F.L., L.E., S.R.S.L San Antonio (A.L.R.), and Houston (C.M.D.), TX, San Antonio State Hospital (S.R.S., A.L.R.L San Antonio, TX, and Kerrviile State Hospital (W.M.S.), Kerrville, TX. Steady-state haloperidol (HL) and reduced HL (RH) plasma levels were measured in Chinese (n = 156), Hispanic (n = 51), Caucasian (n = 37) and Black (n = 23) populations. HL and RH concentrations were assayed by HPLC for Chinese patients and RIA for non-Chinese patients. The con'elation coefficients for HL and RH for HPLC versus ~ A were r = 0.96 (p < 0.02) and r = 0.98 (p < 0.01), respectively. A wide interpatiem variability but positively correlated relationship between HL dose and plasma level was observed for each ethnic group. However, the regression line for the Chinese group differed from the other ethnic populations. HL levels were higher, RH levels were lower, and RH/HL ratios were smaller in Chinese group compared with non-Chinese group. A non-linear relationship between HL and RH plasma concentrations was observed in each ethnic group. A large increase in the RH/HL ratio occurred in both groups when HL doses increased form 40 rag/day to 50 rag/day. The ratios increas~ by a factor of 2.51 and 2.16 in Chinese and non-Chinese groups, respectively. This relationship could reflect a saturation metabofic process in the disposition of HI. and RH. Stepwise regression analysis indicated that dose, RH level, Chinese and Black groups were significant factors that influence HL plasma levels. These results suggest that various ethnic groups could metabolize HL and RH differently.
43
DOSE-DEPENDENT REDUCED HALOPERIDOL/HALOPERIDOL RATIOS IN SCHIZOPHRENIC PATIENTS Wen-Ho Chang, M.D., Hai-Gwo Hwu, M.D., Hsien-Yuan Lane, M.D., Shih-Ku Lin, M.D., Teng-Yi Chen, M.D., Hae-lang Wei, M.D., Wea-Long Lin, M.D., Hsin-N~m Lin, M.D. Taipei Ci~ Psychiatric Center (H.Y.L., S.K.L., T.Y.C.), National Taiwan University Hospital (H.G.H., H.N.L.), and Ma~tary Psychiatric Center (H.L.W, W.L.L.), Taipei, Taiwan, ROC. Haloperidol (HL) and reduced HL (RH) are interconverted. Ketone reductase mediates the conversion of IIL to RH. The RH/HL ratio has been suggested to be an important factor in determining the therapeutic response to HL. Plasma HL and RH levels were measured in 113 Chinese schizophrenic patients (77 men, 36 women; age 30.7 ± 9.8 yrs; weight 55.8 ± 8.0 kg). HL daily closes ranged from 8 to 65 mg. Samples were obtained under steady-state conditions and drawn 10-12 hr. postbedtime dose and prior to the morning dose. A total of 3 ! 3 blood samples were collected. Multiple (2-6) samples were obtained at me same dose in 63 patients and at 2 or 3 different doses in 31 patients. HL and RH levels were assayed by HPLC/ECD. The d~.tection limit was 0.4 ng/ml. The intra- and inter-assay CVs were 4-12% at 2-10 ng/ml. The intc~patient variation in plasma HL levels was wide (up to six-fold difference). However, a highly positive correlation between plasma levels and daily dosages was found (r = 0.85, p < 0.001 in rag/day; r - 0.84, p < 0.001 in mg/kg/day). The equation of HL plasma level (ng/ml) = 0.88 x dosage (mg/day) - 0.56 or 46.0 x dosage (mg/kg/day) + 0.28. The expected values are about 15-55% higher than those obtained
Schizophrenia
BtOL P s v c h ~ v |99| ~:43A- |8$A
63A
from non-Chinese patients as reporte:! in the literatu~. The RI~HL ratios were c l o s e s t . The greater the HL dese used, the higher the RH;HL ratio produced. RH levels ~ . a m e rapidly elevated ~ n doses h~creased from 40 rag/day to 50 rag;day. An upper therapeutic limit of plasma ElL Level is sagges1~ to be 25 ng/ml. Tnis level can be ac~devcd at dosages no~. ~o,ea*.er ~ ~ mgfd~y ~,:,mo~ Chinese ~fients Based on the dose-dependent increase in RI-IL~HLratios, the importance of RH in determ~nring the theralx~c benefit of HL treatment is discussed.
44
NEUROENDOCRINE EFFECT OF FLUPERLAPINE COMP.~d~,ED WITH CHLORPROMAZINE Gyorgy Bartko, M.D., Mihaly Kurcz, Ph.D., Ere Frecska, M.D. National Institute for Nervous and Mental Diseases, Budapest, Hungary: Research Laboratory of Clinical Biochemistry CHINOIN, Budapest, Hungary. Mount Sinai School of Medicine, Clinical Neuroscience Center, Pilgrim Psychiatric Center, West Brentwood, N¥ 11717. Fluperlapine, classified as a tricyclic psychopharmacological agent, chemically resembles the neurolepfics clozapine and clothapine and to the antidepressants amoxapine and d i ~ e p i n e . The efficacy of flupertap~ on the positive, negative, and depressive symptoms of seifizophrenia was clearly demonstrated in s e v ~ clinical studies and it was found to be free of significant extrapyramidal side effects. This study investigates the neuroendocrine profile of fluperlapine compared to chlorprcrnazint:. Eighteen nonfecund f e t e patients with DSM-m-R schizophrenia were randomly and blindly assigned to an oral treatment of fluperlapine or ~hlorpmmazine for a period of 42 days. Blood samples were obtained on Day 0, 3, 7, 14, 2 l, 28, and 42 and plasma levels of prolactin (PRL), adrenocorticotropic hormone (ACTH), growth hormone ~GHL thyroid stimulating hormone (TSH), triiodothyronine (13) (total and free), thyroxine ~T4) ~to~ and free), corfisol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were determined. There were significant differences between the PRL values of the study groups at every time point of the investigation. However, there was no evidence that fluperlapine had relevant influence on anyone of these hormones with the exception of a significant decrease of PRL levels on day 7. The T 3 ~ and T 3 ~ leveh g~,~wed si~;~:.~nt rise during the chlorpromazine treatment between days 14 and 42 and were significantly higher on day 42 in the chlorpromazine group than those in the fluperlapine groups. Together with clinical experiences, these findings suggest that similarly to clozapine and in contrast to typtcai neuroleptics fluperlapine may permit normal dopaminergic function in h'le anterior pituitary region.
45
RECOGNITION DEFICITS IN CHRONIC SCHIZOPHRENICS Barry D. Schwartz, Ph.D., William J. Evans, B.S., Frederic J. Sautter, Ph.D., Daniel K. Winstead, M.D. Tulane University Medical Schoo!, New Orleans, LA. Early information processing deficits are consistently observed for schizophrenics. The focus of this study was to evaluate processing while controlling for several sources of variance (i.e., sex, age, duration of illness, medication, and schizophrenic subtype). A forced-choice task measured the critical stimulus duration (CSD) for letter recognition. The task criteria was 70% (i.e., 7 out of 10), a liberal or 7 consecutive, a conservative criteria. The letters were. initially presented for 1 msec. and then increased to criteria. At present, 13 normal controls, 11 methadone controls, and 33 schizophrenics participated in the study. Analysis revealed no significant differences within groups associated with criteria. Negative schizophrenics, positive schizophrenics, and methdadone controls did not differ from each other, but were si~ificant~y different from normal controls. Schizophrenics with less than 12 months illness duration, did not differ from normal controYs, but required significantly shorter CSDs than schizophrenics with greater than 12 months duration of illness. The results indicate that chronicl,~ significantly impacts on information processing. Implications for schi~,ophrenic processing are discussed.
62A
Schizophrenia
! 991 ;29:43A- 185A
42
COMPARATIVE ANALYSIS OF HALOPERIDOL AND REDUCED HALOPERIDOL PLASMA LEVELS IN DIFFERENT ETHNIC POPULATIONS Wen-Ho Chang, M.D., Michael W. Jann, Pharm.D., Francis Y.F., Lam, Pharm.D., Hai-Gwo Hwu, M.D., Teng-Yi Chen, M.D., ShihKu Lin, M.D., La,-ry Ereshefsky, Phann.D., Stephen R. Saldad, Pharm.D., Ann L. Richards, Pharrn.D., William M. Schulteis, M.D. Taipei Cir.; Psychiatric Center (T.Y.C., S.K.L.), National Faiwan University Hospital (H.G.H.), Taipei, Taiwan, ROC. Mercer University, Atlanta, GA (M.W,I.), The University of Texas, Austin (F.Y.F.L., L.E., S.R.S.L San Antonio (A.L.R.), and Houston (C.M.D.), TX, San Antonio State Hospital (S.R.S., A.L.R.L San Antonio, TX, and Kerrviile State Hospital (W.M.S.), Kerrville, TX. Steady-state haloperidol (HL) and reduced HL (RH) plasma levels were measured in Chinese (n = 156), Hispanic (n = 51), Caucasian (n = 37) and Black (n = 23) populations. HL and RH concentrations were assayed by HPLC for Chinese patients and RIA for non-Chinese patients. The con'elation coefficients for HL and RH for HPLC versus ~ A were r = 0.96 (p < 0.02) and r = 0.98 (p < 0.01), respectively. A wide interpatiem variability but positively correlated relationship between HL dose and plasma level was observed for each ethnic group. However, the regression line for the Chinese group differed from the other ethnic populations. HL levels were higher, RH levels were lower, and RH/HL ratios were smaller in Chinese group compared with non-Chinese group. A non-linear relationship between HL and RH plasma concentrations was observed in each ethnic group. A large increase in the RH/HL ratio occurred in both groups when HL doses increased form 40 rag/day to 50 rag/day. The ratios increas~ by a factor of 2.51 and 2.16 in Chinese and non-Chinese groups, respectively. This relationship could reflect a saturation metabofic process in the disposition of HI. and RH. Stepwise regression analysis indicated that dose, RH level, Chinese and Black groups were significant factors that influence HL plasma levels. These results suggest that various ethnic groups could metabolize HL and RH differently.
43
DOSE-DEPENDENT REDUCED HALOPERIDOL/HALOPERIDOL RATIOS IN SCHIZOPHRENIC PATIENTS Wen-Ho Chang, M.D., Hai-Gwo Hwu, M.D., Hsien-Yuan Lane, M.D., Shih-Ku Lin, M.D., Teng-Yi Chen, M.D., Hae-lang Wei, M.D., Wea-Long Lin, M.D., Hsin-N~m Lin, M.D. Taipei Ci~ Psychiatric Center (H.Y.L., S.K.L., T.Y.C.), National Taiwan University Hospital (H.G.H., H.N.L.), and Ma~tary Psychiatric Center (H.L.W, W.L.L.), Taipei, Taiwan, ROC. Haloperidol (HL) and reduced HL (RH) are interconverted. Ketone reductase mediates the conversion of IIL to RH. The RH/HL ratio has been suggested to be an important factor in determining the therapeutic response to HL. Plasma HL and RH levels were measured in 113 Chinese schizophrenic patients (77 men, 36 women; age 30.7 ± 9.8 yrs; weight 55.8 ± 8.0 kg). HL daily closes ranged from 8 to 65 mg. Samples were obtained under steady-state conditions and drawn 10-12 hr. postbedtime dose and prior to the morning dose. A total of 3 ! 3 blood samples were collected. Multiple (2-6) samples were obtained at me same dose in 63 patients and at 2 or 3 different doses in 31 patients. HL and RH levels were assayed by HPLC/ECD. The d~.tection limit was 0.4 ng/ml. The intra- and inter-assay CVs were 4-12% at 2-10 ng/ml. The intc~patient variation in plasma HL levels was wide (up to six-fold difference). However, a highly positive correlation between plasma levels and daily dosages was found (r = 0.85, p < 0.001 in rag/day; r - 0.84, p < 0.001 in mg/kg/day). The equation of HL plasma level (ng/ml) = 0.88 x dosage (mg/day) - 0.56 or 46.0 x dosage (mg/kg/day) + 0.28. The expected values are about 15-55% higher than those obtained
Schizophrenia
BtOL P s v c h ~ v |99| ~:43A- |8$A
63A
from non-Chinese patients as reporte:! in the literatu~. The RI~HL ratios were c l o s e s t . The greater the HL dese used, the higher the RH;HL ratio produced. RH levels ~ . a m e rapidly elevated ~ n doses h~creased from 40 rag/day to 50 rag;day. An upper therapeutic limit of plasma ElL Level is sagges1~ to be 25 ng/ml. Tnis level can be ac~devcd at dosages no~. ~o,ea*.er ~ ~ mgfd~y ~,:,mo~ Chinese ~fients Based on the dose-dependent increase in RI-IL~HLratios, the importance of RH in determ~nring the theralx~c benefit of HL treatment is discussed.
44
NEUROENDOCRINE EFFECT OF FLUPERLAPINE COMP.~d~,ED WITH CHLORPROMAZINE Gyorgy Bartko, M.D., Mihaly Kurcz, Ph.D., Ere Frecska, M.D. National Institute for Nervous and Mental Diseases, Budapest, Hungary: Research Laboratory of Clinical Biochemistry CHINOIN, Budapest, Hungary. Mount Sinai School of Medicine, Clinical Neuroscience Center, Pilgrim Psychiatric Center, West Brentwood, N¥ 11717. Fluperlapine, classified as a tricyclic psychopharmacological agent, chemically resembles the neurolepfics clozapine and clothapine and to the antidepressants amoxapine and d i ~ e p i n e . The efficacy of flupertap~ on the positive, negative, and depressive symptoms of seifizophrenia was clearly demonstrated in s e v ~ clinical studies and it was found to be free of significant extrapyramidal side effects. This study investigates the neuroendocrine profile of fluperlapine compared to chlorprcrnazint:. Eighteen nonfecund f e t e patients with DSM-m-R schizophrenia were randomly and blindly assigned to an oral treatment of fluperlapine or ~hlorpmmazine for a period of 42 days. Blood samples were obtained on Day 0, 3, 7, 14, 2 l, 28, and 42 and plasma levels of prolactin (PRL), adrenocorticotropic hormone (ACTH), growth hormone ~GHL thyroid stimulating hormone (TSH), triiodothyronine (13) (total and free), thyroxine ~T4) ~to~ and free), corfisol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were determined. There were significant differences between the PRL values of the study groups at every time point of the investigation. However, there was no evidence that fluperlapine had relevant influence on anyone of these hormones with the exception of a significant decrease of PRL levels on day 7. The T 3 ~ and T 3 ~ leveh g~,~wed si~;~:.~nt rise during the chlorpromazine treatment between days 14 and 42 and were significantly higher on day 42 in the chlorpromazine group than those in the fluperlapine groups. Together with clinical experiences, these findings suggest that similarly to clozapine and in contrast to typtcai neuroleptics fluperlapine may permit normal dopaminergic function in h'le anterior pituitary region.
45
RECOGNITION DEFICITS IN CHRONIC SCHIZOPHRENICS Barry D. Schwartz, Ph.D., William J. Evans, B.S., Frederic J. Sautter, Ph.D., Daniel K. Winstead, M.D. Tulane University Medical Schoo!, New Orleans, LA. Early information processing deficits are consistently observed for schizophrenics. The focus of this study was to evaluate processing while controlling for several sources of variance (i.e., sex, age, duration of illness, medication, and schizophrenic subtype). A forced-choice task measured the critical stimulus duration (CSD) for letter recognition. The task criteria was 70% (i.e., 7 out of 10), a liberal or 7 consecutive, a conservative criteria. The letters were. initially presented for 1 msec. and then increased to criteria. At present, 13 normal controls, 11 methadone controls, and 33 schizophrenics participated in the study. Analysis revealed no significant differences within groups associated with criteria. Negative schizophrenics, positive schizophrenics, and methdadone controls did not differ from each other, but were si~ificant~y different from normal controls. Schizophrenics with less than 12 months illness duration, did not differ from normal controYs, but required significantly shorter CSDs than schizophrenics with greater than 12 months duration of illness. The results indicate that chronicl,~ significantly impacts on information processing. Implications for schi~,ophrenic processing are discussed.