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Biologic indices of heterogeneity in schizophrenia: Relationship to psychopathology and treatment outcome
44A
BIOL PSYCHIATRY 19'#1;29:43A-185A
Schizophrenia !
third ventricle, temporal lobes~ ~,lplx~campus, etc. were measured. The patients in the acute treatment groups were significantly younger and had a shorter duration of illness compared to the antipsychotic-refractory patients. The ventricular and other structural volumes were not significantly different between groups. Preliminary analyses indicate that tho~.e patients with lateral ventricle volumes greater than 2 standard deviations above the control mean are more likely to be in the treatment-non-responsive groups. The significance of the results will be discussed.
GATING AND HABITUATION OF THE STARTLE REFLEX IN SCHIZOPHRENIC PATIENTS David L. Braff, Christian Grillon, Joyce Sprock, Neal R. Swerdlow, Mark A. Geyer Department of Ps3.,chiatD', UCSD, La Jolla, CA 92093. Schizophrenic patients have impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have welldescribed neurobiological bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize schizophrenic spectrum patients, in this context, the startle response is particularly interesting, as it is a cross-species, wholebody response to strong stimuli that is plastic or alterable using i~arad~gmatic and neurobiological manipulations. This study utilized 39 schizophrenic patients and 37 normal control subjects who were studied in a new EMG-based startle response paradigm where gating (a CNSbased measure of inhibitory function) and habituation (the normal decrease in response to repeated stimuli over time) can both be assessed in one test session. The results indicate that schizophrenic patients have dramatic deficits in acoustic- and tactile-elicited sensorimotor gating and a strong trend to show habituation deficits. Cumulatively, the results illustrate the wide range of neurobiologically based deficits that characterize schizophrenic patients. Additionally, we will present data on negative and positive symptoms, neuropsychological function, and demographic correlates of the observed deficits. Our knowledge of animal model-derived basic mechanisms of gating and habituation allow us to generate new and specific testable hypotheses about the CNS basis of schizophrenic disorders.
BIOLOGIC INDICES OF HETEROGENEITY IN SCHIZOPHRENIA: RELATIONSHIP TO PSYCHOPATHOLOGY AND TREATMENT OUTCOME Jeffrey Lieberman, M.D., David Mayerhoff, M.D., Antony Loebel, M.D., Gustav Degreef, M.D., Deborah Levy, Ph.D., Jose Alvir, Dr. P.H., Manzar Ashtari, Ph.D., Thomas Cooper, M.A. Department of Psychiatry, Hillside Hospital, Glen Oaks, NY 11004. We have initiated a study of never-treated patients in their first episode of illness in a prospective longitudinal design to characterize biologic deficits prior to neuroleptic exposure and chronic illness effects and to determine their clinical significance. Seventy patients (63% men, mean age 23 - 5.7 years) were ascertained when admitted to hospital for their first episode of schizophrenia and prior to neuroleptic treatment. Patients underwent clinical evaluation, MRI, methylphenidate and epomorphine challenge test, and smooth pursuit eye movement exams under controlled conditions using standardized procedures. Patients received standardized treatment and were followed for up to 3 years with clinical evaluations. Rates of pathobiology for the measures used were: abnormal brain morphology 30%, psychotogenic response to methyl 61%, abnormal SPEM 43%, abnormal basal GH levels (48%) (all rates were statistically significant greater than normal control groups). Eighty-four percent of subjects achieved remission in a mean/median of 35.7/13 weeks. The global outcomes of the sample were: 20% excellent, 21% good, 43% fair, 16% poor. Individual biologic abnormalities were significantly associated with poorer treatment response and outcome. When the combined effects of the biologic variables on treatment outcome were examined, the strength of the correlations (r)
Schizophrenia I
81OL PSYCHIATRY |99| :29:43A- |85A
45A
increased from .45 to .8 (p = 0.01). These and further results on the relationships between t ~ biologic variables and psychopathology and treatment outcome will be presented and discussed.
CONSISTENCY OF PSYCHOPATHOLOGICAL DIMENSIONS IN SCHIZOPHRENIA AS DETERIvlINED BY THE BPRS: A MULTICENTER FACTOR ANALYTIC STUDY R. Goldman, R. Tandon, I. Woodard, W. Faustman, F. Hohagen, W.F. Gattaz, M.S. Keshavan, S. Mukherjee University of Michigan, Ann Arbor, MI 48109-0120, Stanford University, Palo Alto, CA, Central Institute of Mental Health, Mannheim, FRG, University of Pittsburgh, Pittsburgh, PA. New York State Psychiatric Research Institute, New York, NY. There now exists a plethora of specific symptom rating instruments in schizophrenia, but the Brief Psychiatric Rating Scale (BPRS) remains widely used. The BPRS was developed to broadly measure a range of symptoms and predated current concepts of schizophrenic symptom subtypes. The present multiple center study was undertaken to determine the extent to which the BPRS measures four characteri~stic psychopathological dimensions in schizophrenia (positive symptoms, negative symptoms, mood, agitation) and whether these dimensions ,,.~ consistent across centers. A total of 403 well-diagnosed schizophrenic patients across the four centers were administered the 18-item BPRS while drag free. Preliminary findings revealed relatively clear and distinct negative symptom and mood dimensions across the four centers. There was greater overlap between positive symptoms and agitation items. The findings of the confirmatory analytic procedures be discussed in terms of the validity of a dimensionai model of psychopathology in schizophrenia and the role of rating instruments.
SEROTONIN FUNCTION IN TREATMENT OF REFRACTORY SCHIZOPHRENIA M. Davidson, R.S. Kahn, R. Stem, R.F. McQueeny, M. Duffelmeyer, L. Siever, K.L. Davis Department of Psychiatry, Mount Sinai School of Medicine~Bronx Veterans Admim'stration Hospital, New York, NY 19468. Over 20% of schizophrenic patients are refractory to treatment with antidopaminergic drugs. Clozapine, the only compound proven to be effective in these treatment refractory schizophrenics, is a potent serotonin (:SliT) antagonist. This study tested the hypothesis that 5HT dysfunction is related to treatment refractory schizophrenia, using m-cldorophenyl piperazine (MCPP) as a probe to examine 5HT function. Behavioral, neuroendocrine, and temperature responses to MCPP were measured in schizophrenic patients and normal subjects after a 4-week drug-free period. Following this assessment of 5ITf function, patients were treated with haloperidol. The MCPP test was repeated during the 5th week of haloperidol treatment. Patients who failed to respond to haloperidol were then treated with clozapine. The MCPP test was repeated after 5 weeks on clozapine. Preliminary results from this ongoing study suggest that 1) as a group, chronic schizophrenic patients (n = 14) have blunted temperature and behavioral responses to MCPP as compared to normal subjects (n = 13); 2) clozapine, but not haloperidol blocks MCPP-induced ACTH, cortisol, and prolactin release. These results suggest that chronic schizophrenic patients may have blunted 5HT receptor function and suggest that neuroendocrine ~-esponses to MCPP may be used to assess the effects of clozapine on 5HT receptors.
BIOL PSYCHIATRY 19'#1;29:43A-185A
Schizophrenia !
third ventricle, temporal lobes~ ~,lplx~campus, etc. were measured. The patients in the acute treatment groups were significantly younger and had a shorter duration of illness compared to the antipsychotic-refractory patients. The ventricular and other structural volumes were not significantly different between groups. Preliminary analyses indicate that tho~.e patients with lateral ventricle volumes greater than 2 standard deviations above the control mean are more likely to be in the treatment-non-responsive groups. The significance of the results will be discussed.
GATING AND HABITUATION OF THE STARTLE REFLEX IN SCHIZOPHRENIC PATIENTS David L. Braff, Christian Grillon, Joyce Sprock, Neal R. Swerdlow, Mark A. Geyer Department of Ps3.,chiatD', UCSD, La Jolla, CA 92093. Schizophrenic patients have impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have welldescribed neurobiological bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize schizophrenic spectrum patients, in this context, the startle response is particularly interesting, as it is a cross-species, wholebody response to strong stimuli that is plastic or alterable using i~arad~gmatic and neurobiological manipulations. This study utilized 39 schizophrenic patients and 37 normal control subjects who were studied in a new EMG-based startle response paradigm where gating (a CNSbased measure of inhibitory function) and habituation (the normal decrease in response to repeated stimuli over time) can both be assessed in one test session. The results indicate that schizophrenic patients have dramatic deficits in acoustic- and tactile-elicited sensorimotor gating and a strong trend to show habituation deficits. Cumulatively, the results illustrate the wide range of neurobiologically based deficits that characterize schizophrenic patients. Additionally, we will present data on negative and positive symptoms, neuropsychological function, and demographic correlates of the observed deficits. Our knowledge of animal model-derived basic mechanisms of gating and habituation allow us to generate new and specific testable hypotheses about the CNS basis of schizophrenic disorders.
BIOLOGIC INDICES OF HETEROGENEITY IN SCHIZOPHRENIA: RELATIONSHIP TO PSYCHOPATHOLOGY AND TREATMENT OUTCOME Jeffrey Lieberman, M.D., David Mayerhoff, M.D., Antony Loebel, M.D., Gustav Degreef, M.D., Deborah Levy, Ph.D., Jose Alvir, Dr. P.H., Manzar Ashtari, Ph.D., Thomas Cooper, M.A. Department of Psychiatry, Hillside Hospital, Glen Oaks, NY 11004. We have initiated a study of never-treated patients in their first episode of illness in a prospective longitudinal design to characterize biologic deficits prior to neuroleptic exposure and chronic illness effects and to determine their clinical significance. Seventy patients (63% men, mean age 23 - 5.7 years) were ascertained when admitted to hospital for their first episode of schizophrenia and prior to neuroleptic treatment. Patients underwent clinical evaluation, MRI, methylphenidate and epomorphine challenge test, and smooth pursuit eye movement exams under controlled conditions using standardized procedures. Patients received standardized treatment and were followed for up to 3 years with clinical evaluations. Rates of pathobiology for the measures used were: abnormal brain morphology 30%, psychotogenic response to methyl 61%, abnormal SPEM 43%, abnormal basal GH levels (48%) (all rates were statistically significant greater than normal control groups). Eighty-four percent of subjects achieved remission in a mean/median of 35.7/13 weeks. The global outcomes of the sample were: 20% excellent, 21% good, 43% fair, 16% poor. Individual biologic abnormalities were significantly associated with poorer treatment response and outcome. When the combined effects of the biologic variables on treatment outcome were examined, the strength of the correlations (r)
Schizophrenia I
81OL PSYCHIATRY |99| :29:43A- |85A
45A
increased from .45 to .8 (p = 0.01). These and further results on the relationships between t ~ biologic variables and psychopathology and treatment outcome will be presented and discussed.
CONSISTENCY OF PSYCHOPATHOLOGICAL DIMENSIONS IN SCHIZOPHRENIA AS DETERIvlINED BY THE BPRS: A MULTICENTER FACTOR ANALYTIC STUDY R. Goldman, R. Tandon, I. Woodard, W. Faustman, F. Hohagen, W.F. Gattaz, M.S. Keshavan, S. Mukherjee University of Michigan, Ann Arbor, MI 48109-0120, Stanford University, Palo Alto, CA, Central Institute of Mental Health, Mannheim, FRG, University of Pittsburgh, Pittsburgh, PA. New York State Psychiatric Research Institute, New York, NY. There now exists a plethora of specific symptom rating instruments in schizophrenia, but the Brief Psychiatric Rating Scale (BPRS) remains widely used. The BPRS was developed to broadly measure a range of symptoms and predated current concepts of schizophrenic symptom subtypes. The present multiple center study was undertaken to determine the extent to which the BPRS measures four characteri~stic psychopathological dimensions in schizophrenia (positive symptoms, negative symptoms, mood, agitation) and whether these dimensions ,,.~ consistent across centers. A total of 403 well-diagnosed schizophrenic patients across the four centers were administered the 18-item BPRS while drag free. Preliminary findings revealed relatively clear and distinct negative symptom and mood dimensions across the four centers. There was greater overlap between positive symptoms and agitation items. The findings of the confirmatory analytic procedures be discussed in terms of the validity of a dimensionai model of psychopathology in schizophrenia and the role of rating instruments.
SEROTONIN FUNCTION IN TREATMENT OF REFRACTORY SCHIZOPHRENIA M. Davidson, R.S. Kahn, R. Stem, R.F. McQueeny, M. Duffelmeyer, L. Siever, K.L. Davis Department of Psychiatry, Mount Sinai School of Medicine~Bronx Veterans Admim'stration Hospital, New York, NY 19468. Over 20% of schizophrenic patients are refractory to treatment with antidopaminergic drugs. Clozapine, the only compound proven to be effective in these treatment refractory schizophrenics, is a potent serotonin (:SliT) antagonist. This study tested the hypothesis that 5HT dysfunction is related to treatment refractory schizophrenia, using m-cldorophenyl piperazine (MCPP) as a probe to examine 5HT function. Behavioral, neuroendocrine, and temperature responses to MCPP were measured in schizophrenic patients and normal subjects after a 4-week drug-free period. Following this assessment of 5ITf function, patients were treated with haloperidol. The MCPP test was repeated during the 5th week of haloperidol treatment. Patients who failed to respond to haloperidol were then treated with clozapine. The MCPP test was repeated after 5 weeks on clozapine. Preliminary results from this ongoing study suggest that 1) as a group, chronic schizophrenic patients (n = 14) have blunted temperature and behavioral responses to MCPP as compared to normal subjects (n = 13); 2) clozapine, but not haloperidol blocks MCPP-induced ACTH, cortisol, and prolactin release. These results suggest that chronic schizophrenic patients may have blunted 5HT receptor function and suggest that neuroendocrine ~-esponses to MCPP may be used to assess the effects of clozapine on 5HT receptors.