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Axis II personality features and disorder in subjects in the New York high-risk project
284
Changes of the mRNAs for two dopamine D2 receptor isoforms brain by haloperidol or methamphetamine treatment I. Sora*, Y. Fujiwara,
in rat
H. Tomita, H. Ishizu, K. Akiyama, S. Otsuki, H.I. Yamamura
Department of Neuropsychiatry, Okayama UniversityMedical School, Okayama 700, Japan
Dopamine D2 receptors are the targets for drugs used in the treatment of schizophrenia. Binding experiments with radiolabeled ligand have demonstrated that administration of neuroleptics such as haloperidol for long periods increases the number of dopamine D2 receptors in rat brain and chronic administrations of psychostimulants such as methamphetamine decrease the number of the receptors. The cDNA of a rat D2 receptors, D2 (415) has been cloned. The D2 receptor has been shown to have seven transmembrane domains, and to be a member of the superfamily of guanine nucleotide binding protein (G-protein) coupled receptors. The finding was followed by the reports that two D2 receptor isoforms were generated by alternative RNA splicing and there is an interest in the distribution and functions of these isoforms. To investigate changes of the two mRMAs encoding the D2 receptor isoforms by haloperidol or methamphetamine treatment, we performed in situ hybridization histochemistry with the two oligonucleotide probes, an “insert probe” hybridizing to the longer D2 (444) mRNA, and a “spanning probe” hybridizing to the shorter D2 (415) mRNA. Male Sprague-Dawley rats received intraperitoneal injections of haloperidol(1 mg/kg), methamphetamine (4 mg/kg) or saline for 14 days. The present study showed that the observed changes of the mRNAs receptors by haloperidol or methamphetamine treatments were in broad agreement with descriptions of the receptor binding experiments in similar treatment with neuroleptics or psychostimulants. Haloperidol treatment increased the mRNAs for both D2 (415) and D2 (444) receptors, and methamphetarnine treatment decreased both D2 mRNAs. D2 (444) mRNAs were expressed dominantly compared to D2 (415) mRNA in rat striatum with all three treatments, and haloperidol or methamphetamine treatments did not change the distribution of two D2 isoforms mRNA. Both D2 (444) and D2 (444) mRNAs were found in the striatum, accubens nucleus and the substantia nigra (pars compacta).
Axis II personality features and disorder in subjects in the New York High-Risk Project E. Squires-Wheeler*,
L. Erlenmeyer-Kirnling,
U. Hildoff Adamo, A. Bassett, B. Cornblatt,
S. Roberts
New York State Psychiattic Institute, 722 W. I<h Street, New York, NY 10032, U.SA.
Axis II personality features and disorders were introduced in DSM-III as adolescent onset, persistent maladaptive personality dispositions leading to subjective distress and/or vocational or social impairment. While the eleven personality disorder categories were not presumed to be mutually exclusive, three clusters were postulated to be relatively discrete including the odd or eccentric cluster (schizotypal, schizoid and paranoid disorders), the dramatic cluster (borderline, histrionic, antisocial and narcissistic personality disorder) and the fearful cluster (passive-aggressive, dependent, obsessive-compulsive and avoidant personality disorder). Expectations regarding familial aggregation of Axis II features and disorders involve hypotheses regarding links between Axis I disorder and Axis II clusters (both within individuals and within families). For example, schizophrenic disorder in an index case has been associated with an increased rate among first degree relatives of Axis II dramatic features and disorder. To examine independently these expectations, we provide distributions of Axis II features and disorder in three groups of subjects defined by parental clinical status. These subjects are drawn from Sample A of the New York High-Risk Project (NYHRP), which at the present follow-up includes 50 offspring of schizophrenic parents (the HRSz group), 40 offspring of parents with affective disorder (the HRAff group) and 92 offspring of parents without psychiatric disorder (the NC group). Axis II assessments were made on the subjects in adulthood by means of blind, direct interviews using the Personality Disorder Examination (PDE, Loranger et al, 1985). The PDE is a standardized, semi-structured clinical interview for eliciting information relevant to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) personality disorders. The PDE was administered to subjects by clinical psychologists and social workers trained in the use
285
of the instrument. The interviewers were blind to parental diagnostic status and to results of previous clinical assessments of the offspring. Probable and definite thresholds for DSM-III personality disorder criteria and raw dimensional scores are reported by parental diagnostic group. The association between social and vocational functioning and the presence of Axis II features and disorder are also reported. The pattern of comorbidity of Axis II clusters within individuals is reported as a function of parental psychiatric status. Axis II associations with Axis I disorder within families provide clues regarding diagnostic boundaries of putative spectrum disorders and clues regarding shared etiological components.
Evidence of early brain changes in subgroup of twins with schizophrenia E.F. Torrey*, E. Taylor, A. Bowler, S. Bracha, P.O. Quinn, L. Bigelow, K. Rickler, N. Higgins, R.J. Wyatt, 1.1. Gottesman Twin Stady Unit, NIMH Neurosciences
Center at St. Elizabeths Hospital, Washington, DC 20032, USA.
Retrospective and prospective (high risk) studies have consistently shown that a subgroup of individuals who develop schizophrenia are behaviorally and/or neurologically abnormal in childhood. As part of a study of monozygotic twins with schizophrenia and schizoaffective disorder, data on 23 discordant pairs were analyzed to ascertain the age at which one twin began to diverge from the co-twin significantly and permanently in behavior and/or motor skills. An extensive developmental history was obtained by a social worker and, on the basis of that history, an age of divergence assigned. In 7 of the 23 twin pairs (30%) the age of divergence was 5 or under; in all others the age of divergence fell between ages 13 and 23, often as an early manifestation of the onset of the disease. In 5 of the 7 individuals with early age of divergence corroborative information was available to support the family history (e.g., referral of child for testing because of clumsiness). The 7 twins with an early age of divergence were compared with the 16 with a later age of divergence on a variety of measures. There were no differences between the two groups in birth order, birth weight, age of first hospitalization, age at time of testing, clinical symptoms, level of function at time of testing (as measured by Axis V), or neurological findings (including mental status and soft signs). There was a trend for the twins with an early age of divergence to be male (6/7 vs. 8/16; p < 0.18); to have been born in January-April (5/7 vs. 5/16; p < 0.17) and to have a less severe course of illness as measured by total months in hospitals (p c 0.12), better response to neuroleptics (p c 0.12), and lower total lifetime neuroleptic dose (p < 0.04). Significant differences occurred between the two groups; those with an early age of divergence had a greater frequency of family history of psychosis (4/7 vs O/16; p c 0.004, Fisher’s exact, 2-tail); more minor physical anomalies (p < 0.03, paired T-test); and a lower total finger ridge count (p < 0.005; paired T-test). The fact that a subgroup of discordant identical twins who later develop schizophrenia have behavioral and/or neurological abnormalities early in life is consistent with studies of premorbid asociality, high risk studies, and previous twin studies of schizophrenia. It is hypothesized that such a group is genetically more susceptible to perinatal insults to the brain and that some of these insults occur in utero.
Neurodevelopmental
indicators of vulnerability
for schizophrenia
E.F. Walker*, R.J. Lewine Departments of Psychology and Pqhiatty,
Emory University, Atlanta, GA 30322, USA.
Findings from high-risk research suggest that signs of vulnerability to adult-onset schizophrenia may be apparent as early as infancy. However, to date, no prospective studies have related directly-measured, early childhood characteristics of high-risk subjects to adult psychiatric outcome. In a recently initiated project, childhood home movies of adult-onset schizophrenic patients are being used to examine early development. The short term goal is to document the nature and age-at-onset of signs of delay and dysfunction. It is hoped that this information will elucidate the heterogeneity within the schizophrenic syndrome and shed light on etiologic origins.
Changes of the mRNAs for two dopamine D2 receptor isoforms brain by haloperidol or methamphetamine treatment I. Sora*, Y. Fujiwara,
in rat
H. Tomita, H. Ishizu, K. Akiyama, S. Otsuki, H.I. Yamamura
Department of Neuropsychiatry, Okayama UniversityMedical School, Okayama 700, Japan
Dopamine D2 receptors are the targets for drugs used in the treatment of schizophrenia. Binding experiments with radiolabeled ligand have demonstrated that administration of neuroleptics such as haloperidol for long periods increases the number of dopamine D2 receptors in rat brain and chronic administrations of psychostimulants such as methamphetamine decrease the number of the receptors. The cDNA of a rat D2 receptors, D2 (415) has been cloned. The D2 receptor has been shown to have seven transmembrane domains, and to be a member of the superfamily of guanine nucleotide binding protein (G-protein) coupled receptors. The finding was followed by the reports that two D2 receptor isoforms were generated by alternative RNA splicing and there is an interest in the distribution and functions of these isoforms. To investigate changes of the two mRMAs encoding the D2 receptor isoforms by haloperidol or methamphetamine treatment, we performed in situ hybridization histochemistry with the two oligonucleotide probes, an “insert probe” hybridizing to the longer D2 (444) mRNA, and a “spanning probe” hybridizing to the shorter D2 (415) mRNA. Male Sprague-Dawley rats received intraperitoneal injections of haloperidol(1 mg/kg), methamphetamine (4 mg/kg) or saline for 14 days. The present study showed that the observed changes of the mRNAs receptors by haloperidol or methamphetamine treatments were in broad agreement with descriptions of the receptor binding experiments in similar treatment with neuroleptics or psychostimulants. Haloperidol treatment increased the mRNAs for both D2 (415) and D2 (444) receptors, and methamphetarnine treatment decreased both D2 mRNAs. D2 (444) mRNAs were expressed dominantly compared to D2 (415) mRNA in rat striatum with all three treatments, and haloperidol or methamphetamine treatments did not change the distribution of two D2 isoforms mRNA. Both D2 (444) and D2 (444) mRNAs were found in the striatum, accubens nucleus and the substantia nigra (pars compacta).
Axis II personality features and disorder in subjects in the New York High-Risk Project E. Squires-Wheeler*,
L. Erlenmeyer-Kirnling,
U. Hildoff Adamo, A. Bassett, B. Cornblatt,
S. Roberts
New York State Psychiattic Institute, 722 W. I<h Street, New York, NY 10032, U.SA.
Axis II personality features and disorders were introduced in DSM-III as adolescent onset, persistent maladaptive personality dispositions leading to subjective distress and/or vocational or social impairment. While the eleven personality disorder categories were not presumed to be mutually exclusive, three clusters were postulated to be relatively discrete including the odd or eccentric cluster (schizotypal, schizoid and paranoid disorders), the dramatic cluster (borderline, histrionic, antisocial and narcissistic personality disorder) and the fearful cluster (passive-aggressive, dependent, obsessive-compulsive and avoidant personality disorder). Expectations regarding familial aggregation of Axis II features and disorders involve hypotheses regarding links between Axis I disorder and Axis II clusters (both within individuals and within families). For example, schizophrenic disorder in an index case has been associated with an increased rate among first degree relatives of Axis II dramatic features and disorder. To examine independently these expectations, we provide distributions of Axis II features and disorder in three groups of subjects defined by parental clinical status. These subjects are drawn from Sample A of the New York High-Risk Project (NYHRP), which at the present follow-up includes 50 offspring of schizophrenic parents (the HRSz group), 40 offspring of parents with affective disorder (the HRAff group) and 92 offspring of parents without psychiatric disorder (the NC group). Axis II assessments were made on the subjects in adulthood by means of blind, direct interviews using the Personality Disorder Examination (PDE, Loranger et al, 1985). The PDE is a standardized, semi-structured clinical interview for eliciting information relevant to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) personality disorders. The PDE was administered to subjects by clinical psychologists and social workers trained in the use
285
of the instrument. The interviewers were blind to parental diagnostic status and to results of previous clinical assessments of the offspring. Probable and definite thresholds for DSM-III personality disorder criteria and raw dimensional scores are reported by parental diagnostic group. The association between social and vocational functioning and the presence of Axis II features and disorder are also reported. The pattern of comorbidity of Axis II clusters within individuals is reported as a function of parental psychiatric status. Axis II associations with Axis I disorder within families provide clues regarding diagnostic boundaries of putative spectrum disorders and clues regarding shared etiological components.
Evidence of early brain changes in subgroup of twins with schizophrenia E.F. Torrey*, E. Taylor, A. Bowler, S. Bracha, P.O. Quinn, L. Bigelow, K. Rickler, N. Higgins, R.J. Wyatt, 1.1. Gottesman Twin Stady Unit, NIMH Neurosciences
Center at St. Elizabeths Hospital, Washington, DC 20032, USA.
Retrospective and prospective (high risk) studies have consistently shown that a subgroup of individuals who develop schizophrenia are behaviorally and/or neurologically abnormal in childhood. As part of a study of monozygotic twins with schizophrenia and schizoaffective disorder, data on 23 discordant pairs were analyzed to ascertain the age at which one twin began to diverge from the co-twin significantly and permanently in behavior and/or motor skills. An extensive developmental history was obtained by a social worker and, on the basis of that history, an age of divergence assigned. In 7 of the 23 twin pairs (30%) the age of divergence was 5 or under; in all others the age of divergence fell between ages 13 and 23, often as an early manifestation of the onset of the disease. In 5 of the 7 individuals with early age of divergence corroborative information was available to support the family history (e.g., referral of child for testing because of clumsiness). The 7 twins with an early age of divergence were compared with the 16 with a later age of divergence on a variety of measures. There were no differences between the two groups in birth order, birth weight, age of first hospitalization, age at time of testing, clinical symptoms, level of function at time of testing (as measured by Axis V), or neurological findings (including mental status and soft signs). There was a trend for the twins with an early age of divergence to be male (6/7 vs. 8/16; p < 0.18); to have been born in January-April (5/7 vs. 5/16; p < 0.17) and to have a less severe course of illness as measured by total months in hospitals (p c 0.12), better response to neuroleptics (p c 0.12), and lower total lifetime neuroleptic dose (p < 0.04). Significant differences occurred between the two groups; those with an early age of divergence had a greater frequency of family history of psychosis (4/7 vs O/16; p c 0.004, Fisher’s exact, 2-tail); more minor physical anomalies (p < 0.03, paired T-test); and a lower total finger ridge count (p < 0.005; paired T-test). The fact that a subgroup of discordant identical twins who later develop schizophrenia have behavioral and/or neurological abnormalities early in life is consistent with studies of premorbid asociality, high risk studies, and previous twin studies of schizophrenia. It is hypothesized that such a group is genetically more susceptible to perinatal insults to the brain and that some of these insults occur in utero.
Neurodevelopmental
indicators of vulnerability
for schizophrenia
E.F. Walker*, R.J. Lewine Departments of Psychology and Pqhiatty,
Emory University, Atlanta, GA 30322, USA.
Findings from high-risk research suggest that signs of vulnerability to adult-onset schizophrenia may be apparent as early as infancy. However, to date, no prospective studies have related directly-measured, early childhood characteristics of high-risk subjects to adult psychiatric outcome. In a recently initiated project, childhood home movies of adult-onset schizophrenic patients are being used to examine early development. The short term goal is to document the nature and age-at-onset of signs of delay and dysfunction. It is hoped that this information will elucidate the heterogeneity within the schizophrenic syndrome and shed light on etiologic origins.