1Psychiatry Clin. Neurosci. 2000 Aug 54: 413-7
PMID10997857
TitleRelationships between age of onset, antisocial history and general psychopathological traits in Japanese alcoholics.
AbstractThis study investigated the relationships of age of onset, antisocial history and general psychopathological traits measured by the Minnesota MultiphaSIc Personality Inventory (MMPI) in Japanese alcoholics (n = 84). A 2 (earlier vs later onset) x 2 (antisocial vs non-antisocial) multivariate analySIs of covariance showed that age of onset had a SIgnificant correlation with some subscales of the MMPI such as L (lie), Sc (schizophrenia), and SI (social introverSIon), whereas history of antisocial behavior had no SIgnificant correlation with any MMPI clinical subscales. This result indicated that age of onset was a more SIgnificant variable than was antisocial history with regard to the current general psychopathological traits on MMPI in Japanese alcoholics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
2J Pers Assess 2000 Jun 74: 439-46
PMID10900570
TitlePsychological needs associated with MMPI-2 scales in a nonclinical sample.
AbstractThe psychological needs derived from the Adjective Check List (ACL; Gough & Heilbrun, 1983b) that are associated with MMPI-2 scales were studied among 198 nonclinical participants. Both the DepresSIon (D) and Psychasthenia (Pt) scales were negatively correlated with needs for achievement and dominance and poSItively correlated with needs for abasement and succorance (dependence). The schizophrenia (Sc) scale was negatively associated with need for affiliation and poSItively associated with need for abasement. The Social IntroverSIon (SI) scale was associated negatively with needs for achievement, dominance, affiliation, heterosexuality, exhibition, and autonomy and associated poSItively with needs for succorance, abasement, and deference, reflecting good construct validity for Scale SI. MMPI-2 Masculinity-Femininity (Mf) did not correlate with the ACL Masculinity and Femininity scales, suggesting poor concurrent validity for Mf.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
3Behav. Brain Res. 2001 Jun 121: 207-18
PMID11275298
TitleDissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague--Dawley rats.
AbstractHuman attentional impairments can be modelled in the rat uSIng the prepulse inhibition (PPI) or the latent inhibition (LI) paradigm. The present study investigated the consequences of a combination of pre-weaning maternal separation (MS) and post-weaning social isolation (SI) on both PPI and LI in male and female Sprague--Dawley rats tested as adults. We report here a double dissociation between the effects of MS (repeated 4 h daily separations) and SI on PPI and LI: MS did not modify PPI, but enhanced LI. In contrast, SI disrupted PPI, the deficits being restricted to male rats, but left LI intact. There were no additive effects of MS and SI on PPI or LI. While MS improved avoidance learning, SI impaired it. Although both PPI and LI assess processes of selective attention, our results support the contention, already stated in the literature, that they involve differing neuro-psychological mechanisms. Furthermore, the fact that only males exhibited PPI deficits following SI has implications for the well-known differential vulnerability of human males to certain psychiatric disorders (e.g. schizophrenia). Finally, the combination of MS and SI could represent a relevant animal model for some aspects of schizophrenia, SInce both PPI and LI were altered.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
4Zhonghua Nei Ke Za Zhi 2001 Dec 40: 806-8
PMID16206667
Title[The result of testing psychotic disorder patients in general hospital with Minnesota Multiphasic Personality Inventory].
AbstractTo study the psychological characteristics of patients with psychotic disorder in general hospital.
92 male and 158 female patients with psychotic disorder were tested with Minnesota multiphaSIc personality inventory (MMPI). They conSIst of 215 cases with neuroSIs (hypochondriaSIs, depresSIon, anxiety, obsesSIve-compulSIve disorder, hysteria, neurasthenia); 4 cases with schizoaffective disorder; 3 cases with manic-depresSIve insanity. 5 cases with schizophrenia and 23 cases of somatoform disease with affective disorder.
The scores of F, K, Hs, D, Hy, Pd, Pa, Pt and SI scales in the patients were SIgnificantly higher than those in normal controls. The scores of Mf were SIgnificantly higher in the male han those in the female patients and the scores of F lower in the male than those in the female patients.
The psychotic disorders as well as seen in patients in general hospital are hypochondriaSIs and somatoform disorder, and depresSIon of the female.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
5Psychiatry Clin. Neurosci. 2002 Aug 56: 443-52
PMID12109963
TitleMinnesota Multiphasic Personality Inventory profile characteristics of schizotypal personality disorder.
AbstractThe goal of the present study was to determine whether precursors for psychopathology can be found in personality dimenSIons of the general population. Two hundred and 62 univerSIty students were compared with 41 schizophrenic patients and 18 patients with schizotypal personality disorder (SPD) on the Minnesota MultiphaSIc Personality Inventory (MMPI). schizotypal personality disorder patients showed SIgnificantly elevated Pt and SI scales compared with the schizophrenic patients. schizophrenia and SPD groups generally produced two-point codetypes of 6-8/8-6, 2-6/6-2, 7-8/8-7, and 7-8/8-7, 2-7/7-2, 6-8/8-6. A total of 77.5% of students had no codetype with a T-value of > or = 70, although the frequency of codetypes of spike 5, spike 0 and 2-7/7-2 was relatively high in the student group compared with the general population. Discriminant function analySIs of the MMPI profiles revealed SIgnificant variance among the three groups. The overall rate of correct clasSIfication of the subjects into schizophrenia, SPD or univerSIty students was 90.3%. The first coefficient, mainly defined by a negative weight on the Sc scale, best distinguished the patients with either schizophrenia or SPD from the students. The second coefficient, defined by negative weights on the Sc and SI scales, and poSItive weights on the F and Ma scales identified patients with schizophrenia and SPD patients. The Harris-Lingoes subscales, which are supposed to provide the profile patterns characteristic of schizotypy, well discriminated the three groups. These results suggest the usefulness of the MMPI subscales for the detection of subjects with the SPD trait.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
6Psychiatry Clin. Neurosci. 2002 Aug 56: 443-52
PMID12109963
TitleMinnesota Multiphasic Personality Inventory profile characteristics of schizotypal personality disorder.
AbstractThe goal of the present study was to determine whether precursors for psychopathology can be found in personality dimenSIons of the general population. Two hundred and 62 univerSIty students were compared with 41 schizophrenic patients and 18 patients with schizotypal personality disorder (SPD) on the Minnesota MultiphaSIc Personality Inventory (MMPI). schizotypal personality disorder patients showed SIgnificantly elevated Pt and SI scales compared with the schizophrenic patients. schizophrenia and SPD groups generally produced two-point codetypes of 6-8/8-6, 2-6/6-2, 7-8/8-7, and 7-8/8-7, 2-7/7-2, 6-8/8-6. A total of 77.5% of students had no codetype with a T-value of > or = 70, although the frequency of codetypes of spike 5, spike 0 and 2-7/7-2 was relatively high in the student group compared with the general population. Discriminant function analySIs of the MMPI profiles revealed SIgnificant variance among the three groups. The overall rate of correct clasSIfication of the subjects into schizophrenia, SPD or univerSIty students was 90.3%. The first coefficient, mainly defined by a negative weight on the Sc scale, best distinguished the patients with either schizophrenia or SPD from the students. The second coefficient, defined by negative weights on the Sc and SI scales, and poSItive weights on the F and Ma scales identified patients with schizophrenia and SPD patients. The Harris-Lingoes subscales, which are supposed to provide the profile patterns characteristic of schizotypy, well discriminated the three groups. These results suggest the usefulness of the MMPI subscales for the detection of subjects with the SPD trait.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
7Psychiatry Clin. Neurosci. 2002 Aug 56: 443-52
PMID12109963
TitleMinnesota Multiphasic Personality Inventory profile characteristics of schizotypal personality disorder.
AbstractThe goal of the present study was to determine whether precursors for psychopathology can be found in personality dimenSIons of the general population. Two hundred and 62 univerSIty students were compared with 41 schizophrenic patients and 18 patients with schizotypal personality disorder (SPD) on the Minnesota MultiphaSIc Personality Inventory (MMPI). schizotypal personality disorder patients showed SIgnificantly elevated Pt and SI scales compared with the schizophrenic patients. schizophrenia and SPD groups generally produced two-point codetypes of 6-8/8-6, 2-6/6-2, 7-8/8-7, and 7-8/8-7, 2-7/7-2, 6-8/8-6. A total of 77.5% of students had no codetype with a T-value of > or = 70, although the frequency of codetypes of spike 5, spike 0 and 2-7/7-2 was relatively high in the student group compared with the general population. Discriminant function analySIs of the MMPI profiles revealed SIgnificant variance among the three groups. The overall rate of correct clasSIfication of the subjects into schizophrenia, SPD or univerSIty students was 90.3%. The first coefficient, mainly defined by a negative weight on the Sc scale, best distinguished the patients with either schizophrenia or SPD from the students. The second coefficient, defined by negative weights on the Sc and SI scales, and poSItive weights on the F and Ma scales identified patients with schizophrenia and SPD patients. The Harris-Lingoes subscales, which are supposed to provide the profile patterns characteristic of schizotypy, well discriminated the three groups. These results suggest the usefulness of the MMPI subscales for the detection of subjects with the SPD trait.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
8Neuropharmacology 2002 Mar 42: 414-20
PMID11897119
TitleNeonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs.
AbstractNitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogeneSIs during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's senSItivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly baSIs for at least five weeks. Haloperidol failed to SIgnificantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to SIgnificantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential senSItivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more senSItive to atypical antipsychotics rather than haloperidol.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
9Psychiatry Clin. Neurosci. 2002 Aug 56: 443-52
PMID12109963
TitleMinnesota Multiphasic Personality Inventory profile characteristics of schizotypal personality disorder.
AbstractThe goal of the present study was to determine whether precursors for psychopathology can be found in personality dimenSIons of the general population. Two hundred and 62 univerSIty students were compared with 41 schizophrenic patients and 18 patients with schizotypal personality disorder (SPD) on the Minnesota MultiphaSIc Personality Inventory (MMPI). schizotypal personality disorder patients showed SIgnificantly elevated Pt and SI scales compared with the schizophrenic patients. schizophrenia and SPD groups generally produced two-point codetypes of 6-8/8-6, 2-6/6-2, 7-8/8-7, and 7-8/8-7, 2-7/7-2, 6-8/8-6. A total of 77.5% of students had no codetype with a T-value of > or = 70, although the frequency of codetypes of spike 5, spike 0 and 2-7/7-2 was relatively high in the student group compared with the general population. Discriminant function analySIs of the MMPI profiles revealed SIgnificant variance among the three groups. The overall rate of correct clasSIfication of the subjects into schizophrenia, SPD or univerSIty students was 90.3%. The first coefficient, mainly defined by a negative weight on the Sc scale, best distinguished the patients with either schizophrenia or SPD from the students. The second coefficient, defined by negative weights on the Sc and SI scales, and poSItive weights on the F and Ma scales identified patients with schizophrenia and SPD patients. The Harris-Lingoes subscales, which are supposed to provide the profile patterns characteristic of schizotypy, well discriminated the three groups. These results suggest the usefulness of the MMPI subscales for the detection of subjects with the SPD trait.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
10Psychiatry Clin. Neurosci. 2004 Oct 58: 507-15
PMID15482582
TitleCan a less pejorative Chinese translation for schizophrenia reduce stigma? A study of adolescents' attitudes toward people with schizophrenia.
AbstractThe term jing-shen-fen-lie-zheng (mind-split-disease) has been used to denote schizophrenia in Chinese societies. Many ASIan countries, where the Chinese writing system is used, adopt a SImilar translation. This study examined whether a less pejorative name SI-jue-shi-diao (dys-regulation of thought and perception) as a diagnostic label for symptoms of schizophrenia could reduce stigma. Secondary school students (n = 313) were randomly asSIgned to read a vignette with one of four labels: SI-jue-shi-diao, jing-shen-fen-lie-zheng, jing-shen-bin (mental illness), and no label. Students expressed their social distance, stereotypes held, and attributions toward a young adult who met the Diagnostic and Statistical Manual-IV of Mental Health Disorders criteria for schizophrenia. It was found that psychiatric labeling did not have a statistically SIgnificant main effect on attitude measures. However, students with religious beliefs were more accepting toward the target individual associated with diagnostic label than one with no labeling. The results cast doubts that less pejorative labels can reduce the social stigma of schizophrenia. Some potential drawbacks in uSIng politically correct terms to describe schizophrenia are highlighted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
11Neuroreport 2004 Jan 15: 155-9
PMID15106849
TitleGamma/beta oscillation and sensory gating deficit in schizophrenia.
AbstractSensory gating can be measured by the suppresSIon of auditory evoked potentials in a paired-click paradigm. The normal gating of the P50 response to the second stimulus (S2) is impaired in many schizophrenic patients. Various in vitro and in vivo evoked potential paradigms have shown that a stimulus evokes early gamma frequency oscillation, which is followed by beta frequency oscillation. The gamma-to-beta shift in response to the first stimulus (SI) in the paired-click paradigm may contain critical electrophySIological SIgnals that modulate the S2 suppresSIon. The results of the present study showed that post-SI beta frequency response was inversely correlated to the S2 P50 response in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
12Neuroreport 2004 Jan 15: 155-9
PMID15106849
TitleGamma/beta oscillation and sensory gating deficit in schizophrenia.
AbstractSensory gating can be measured by the suppresSIon of auditory evoked potentials in a paired-click paradigm. The normal gating of the P50 response to the second stimulus (S2) is impaired in many schizophrenic patients. Various in vitro and in vivo evoked potential paradigms have shown that a stimulus evokes early gamma frequency oscillation, which is followed by beta frequency oscillation. The gamma-to-beta shift in response to the first stimulus (SI) in the paired-click paradigm may contain critical electrophySIological SIgnals that modulate the S2 suppresSIon. The results of the present study showed that post-SI beta frequency response was inversely correlated to the S2 P50 response in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
13Schizophr. Res. 2004 Apr 67: 277-82
PMID14984888
TitleAbnormalities in MRI-measured signal intensity in the corpus callosum in schizophrenia.
AbstractThe microstructural integrity of the corpus callosum (CC) in first-episode schizophrenia patients was assessed by measuring the SIgnal intenSIty (SI) in T1-weighted MRI images. Analyses revealed that compared to both healthy controls and non-schizophrenic patients, schizophrenia patients showed reductions in SI in all the callosal subregions, the genu, body, isthmus and splenium in first-episode schizophrenia. These results indicate that schizophrenia is characterized by pathology of this principal interhemispheric commissure; the abnormalities may reflect distributed (rather than localized) interhemispheric disconnectivity that extends beyond the heteromodal association cortices.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
14Schizophr. Res. 2004 Apr 67: 277-82
PMID14984888
TitleAbnormalities in MRI-measured signal intensity in the corpus callosum in schizophrenia.
AbstractThe microstructural integrity of the corpus callosum (CC) in first-episode schizophrenia patients was assessed by measuring the SIgnal intenSIty (SI) in T1-weighted MRI images. Analyses revealed that compared to both healthy controls and non-schizophrenic patients, schizophrenia patients showed reductions in SI in all the callosal subregions, the genu, body, isthmus and splenium in first-episode schizophrenia. These results indicate that schizophrenia is characterized by pathology of this principal interhemispheric commissure; the abnormalities may reflect distributed (rather than localized) interhemispheric disconnectivity that extends beyond the heteromodal association cortices.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
15Psychopharmacology (Berl.) 2004 Nov 176: 312-9
PMID15179541
TitleChronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia.
AbstractThe rat neonatal ventral hippocampal (VH) ibotenic leSIon model has been proposed as a developmental model of schizophrenia, based on evidence that it encompasses aspects of the disorder including psychomotor agitation (hyperactivity), deficits in prepulse inhibition (PPI), and deficits in social interaction (SI), measures presumed to reflect poSItive symptoms, sensory gating deficits and negative symptoms, respectively. However, validation of the model as a predictive pharmacological screening tool has been minimal.
Determine the effects of a chronic 3-week low dose treatment of clozapine or risperidone on locomotor hyperactivity, PPI and SI in leSIoned and control rats.
Both clozapine, 2.5 mg/kg per day IP and risperidone, 0.1 mg/kg per day IP, reversed leSIon-induced locomotor hyperactivity; however, the compounds also decreased locomotor activity in the non-leSIoned controls. Clozapine 2.5 mg/kg per day and risperidone 0.1 mg/kg per day SIgnificantly attenuated leSIon-induced PPI deficits. Neither compound induced a SIgnificant attenuation of leSIon-induced SI deficits. In order to see if SI deficits required a higher dose of an antipsychotic, the dose of clozapine was increased to 4 mg/kg per day; however this dose induced such marked decreases in the activity and startle responses in the control rats, i.e. up to 74% decrease, that the effects on the leSIoned rats could not be adequately interpreted.
These data add further support to the neonatal VH leSIon model as a predictive pharmacological screening assay for identifying compounds effective in the treatment of poSItive symptoms of schizophrenia. However, the usefulness of the model in detecting compounds effective in treating negative symptoms of schizophrenia is still in question.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
16Biol. Psychiatry 2004 Jan 55: 177-84
PMID14732598
TitleShape of caudate nucleus and its cognitive correlates in neuroleptic-naive schizotypal personality disorder.
AbstractWe measured the shape of the head of the caudate nucleus with a new approach based on magnetic resonance imaging (MRI) in schizotypal personality disorder (SPD) subjects in whom we previously reported decreased caudate nucleus volume. We believe MRI shape analySIs complements traditional MRI volume measurements.
Magnetic resonance imaging scans were used to measure the shape of the caudate nucleus in 15 right-handed male subjects with SPD, who had no prior neuroleptic exposure, and in 14 matched normal comparison subjects. With MRI procesSIng tools, we measured the head of the caudate nucleus uSIng a shape index, which measured how much a given shape deviates from a sphere.
In relation to comparison subjects, neuroleptic never-medicated SPD subjects had SIgnificantly higher (more "edgy") head of the caudate shape index scores, lateralized to the right SIde. Additionally, for SPD subjects, higher right and left head of the caudate SI scores correlated SIgnificantly with poorer neuropsychological performance on tasks of visuospatial memory and auditory/verbal working memory, respectively.
These data confirm the value of measuring shape, as well as volume, of brain regions of interest and support the association of intrinSIc pathology in the caudate nucleus, unrelated to neuroleptic medication, with cognitive abnormalities in the schizophrenia spectrum.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
17Biol. Psychiatry 2004 Jan 55: 177-84
PMID14732598
TitleShape of caudate nucleus and its cognitive correlates in neuroleptic-naive schizotypal personality disorder.
AbstractWe measured the shape of the head of the caudate nucleus with a new approach based on magnetic resonance imaging (MRI) in schizotypal personality disorder (SPD) subjects in whom we previously reported decreased caudate nucleus volume. We believe MRI shape analySIs complements traditional MRI volume measurements.
Magnetic resonance imaging scans were used to measure the shape of the caudate nucleus in 15 right-handed male subjects with SPD, who had no prior neuroleptic exposure, and in 14 matched normal comparison subjects. With MRI procesSIng tools, we measured the head of the caudate nucleus uSIng a shape index, which measured how much a given shape deviates from a sphere.
In relation to comparison subjects, neuroleptic never-medicated SPD subjects had SIgnificantly higher (more "edgy") head of the caudate shape index scores, lateralized to the right SIde. Additionally, for SPD subjects, higher right and left head of the caudate SI scores correlated SIgnificantly with poorer neuropsychological performance on tasks of visuospatial memory and auditory/verbal working memory, respectively.
These data confirm the value of measuring shape, as well as volume, of brain regions of interest and support the association of intrinSIc pathology in the caudate nucleus, unrelated to neuroleptic medication, with cognitive abnormalities in the schizophrenia spectrum.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
18Biol. Psychiatry 2005 Mar 57: 500-9
PMID15737665
TitleValproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
AbstractReelin and GAD(67) expresSIon is downregulated in cortical interneurons of schizophrenia (SZ) patients. This downregulation is probably mediated by epigenetic hypermethylation of the respective promoters caused by the selective increase of DNA-methyltransferase 1 in GABAergic neurons. Mice receiving methionine (MET) provide an epigenetic model for neuropathologies related to SZ. We studied whether MET-induced epigenetic reelin promoter hypermethylation and the associated behavioral alterations can be reduced by valproate in doses that inhibit histone deacetylases (HDACs).
Mice treated with either methionine (MET) (5.2 mmol/kg/SC/twice daily) or valproate (1.5 mmol/kg/SC/twice daily) or MET+ valproate combination were tested for prepulse inhibition of startle (PPI) and social interaction (SI). S-adenosylmethionine, acetylated histone 3, reelin promoter methylation, and reelin mRNA were assayed in the frontal cortex.
Valproate enhances acetylated histone 3 content, and prevents MET-induced reelin promoter hypermethylation, reelin mRNA downregulation, and PPI and SI deficits. Imidazenil, a poSItive allosteric modulator at GABA(A) receptors containing alpha(5) subunits but inactive at receptors including alpha(1) subunits, normalizes MET-induced behavioral changes.
This MET-induced epigenetic mouse models the neurochemical and behavioral aspects of SZ that can be corrected by poSItively modulating the action of GABA at alpha(5)-containing GABA(A) receptors with imidazenil or by inhibiting HDACs with valproate, thus opening exciting new avenues for treatment of epigenetically modified chromatin in SZ morbidity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
19Neuroimage 2005 Jun 26: 502-12
PMID15907307
TitleQuantitative analysis of group-specific brain tissue probability map for schizophrenic patients.
AbstractWe developed group-specific tissue probability map (TPM) for gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) on the common spatial coordinates of an averaged brain atlas derived from normal controls (NC) and from schizophrenic patients (SZ). To identify differences in group-specific TPMs, we used quantitative evaluation methods based on differences in probabilistic distribution as a global criterion, and the mean probability and the SImilarity index (SI) by lobe as regional criteria. The SZ group showed more spatial variation with a lower mean probability than NC subjects. And, for the right temporal and left parietal lobes, the SI between each group was lower than the other lobes. It can be said that there were SIgnificant differences in spatial distribution between controls and schizophrenic patients at those areas. In case of female group, although group differences in the volumes of GM and WM were not SIgnificant, global difference in the probabilistic distribution of GM was more prominent and the SI was lower and its descent rate was greater in all lobes, compared with the male group. If these morphological differences caused by disease or group-specific features were not conSIdered in TPM, the accuracy and certainty of specific group studies would be greatly reduced. Therefore, suitable TPM is required as a common framework for functional neuroimaging studies and an a priori knowledge of tissue clasSIfication.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
20Protein Sci. 2006 Dec 15: 2708-17
PMID17088322
TitleCrystal structure of human D-amino acid oxidase: context-dependent variability of the backbone conformation of the VAAGL hydrophobic stretch located at the si-face of the flavin ring.
AbstractIn the brain, the extenSIvely studied FAD-dependent enzyme D-amino acid oxidase (DAO) degrades the gliotransmitter D-serine, a potent activator of N-methyl-D-aspartate type glutamate receptors, and evidence suggests that DAO, together with its activator G72 protein, may play a key role in the pathophySIology of schizophrenia. Indeed, its potential clinical importance highlights the need for structural and functional analyses of human DAO. We recently succeeded in purifying human DAO, and found that it weakly binds FAD and shows a SIgnificant slower rate of flavin reduction compared with porcine DAO. However, the molecular baSIs for the different kinetic features remains unclear because the active SIte of human DAO was conSIdered to be virtually identical to that of porcine DAO, as would be expected from the 85% sequence identity. To address this issue, we determined the crystal structure of human DAO in complex with a competitive inhibitor benzoate, at a resolution of 2.5 Angstrom. The overall dimeric structure of human DAO is SImilar to porcine DAO, and the catalytic reSIdues are fully conserved at the re-face of the flavin ring. However, at the SI-face of the flavin ring, despite the strict sequence identity, a hydrophobic stretch (reSIdues 47-51, VAAGL) exists in a SIgnificantly different conformation compared with both of the independently determined porcine DAO-benzoate structures. This suggests that a context-dependent conformational variability of the hydrophobic stretch accounts for the low affinity for FAD as well as the slower rate of flavin reduction, thus highlighting the unique features of the human enzyme.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
21J Clin Psychiatry 2006 May 67: 789-97
PMID16841629
TitleGlucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis.
AbstractClozapine and olanzapine treatment has been associated with insulin reSIstance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism.
A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls uSIng a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analySIs (7 quetiapine, 8 olanzapine, 9 normal controls).
There was a SIgnificant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin senSItivity index (SI) differed SIgnificantly among groups (p = .039); olanzapine subjects exhibited SIgnificant insulin reSIstance compared to normal controls (p = .01), but there was no SIgnificant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin reSIstance calculated by the homeostaSIs model assessment of insulin reSIstance (HOMA-IR) also differed SIgnificantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a SIgnificant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049).
Our findings are conSIstent with our previous report that nonobese olanzapine-treated subjects showed insulin reSIstance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
22Chem Rec 2007 -1 7: 305-15
PMID17924443
TitleHuman D-amino acid oxidase: an update and review.
AbstractThe flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophySIology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosyntheSIs in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (reSIdues 47-51, structurally ambivalent peptide) located at the SI-face of the flavin ring assumes a uniquely stable conformation, which provides a structural baSIs for the unique kinetic features of human DAO.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
23Psychopharmacology (Berl.) 2007 Jun 192: 325-36
PMID17333138
TitleHeterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol.
AbstractCannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia.
The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Delta(9)-tetrahydrocannabinol (THC), the major psychotropic component of cannabis.
Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested uSIng open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests.
Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more senSItive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests.
Nrg1 HET mice were more senSItive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the senSItivity to the behavioural effects of cannabinoids.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
24Psychiatry Res 2007 Jun 151: 189-99
PMID17412427
TitleImpaired secondary somatosensory gating in patients with schizophrenia.
AbstractA large and growing literature has demonstrated a deficit in auditory gating in patients with schizophrenia. Although that deficit has been interpreted as a general gating problem, no deficit has been shown in other sensory modalities. Recent research in our laboratory has examined sensory gating effects in the somatosensory system showing no difference in gating of the primary somatosensory response between patients with schizophrenia and control subjects. This is conSIstent with recent structural studies showing no cortical structural abnormality in primary somatosensory area in schizophrenia. However, a SIgnificant decrease in cortical thickness and gray matter volume loss in secondary somatosensory cortex has recently been reported, suggesting this as a focus for impaired somatosensory gating. Thus, the current study was deSIgned (1) to replicate previous work showing a lack of schizophrenia deficit in primary somatosensory cortex (SI) gating, and (2) to investigate a posSIble deficit in secondary somatosensory cortex (SII) gating. In a paired-pulse paradigm, dipolar sources were assessed in SI and SII contralateral to unilateral median nerve stimulation. Patients demonstrated no impairment in SI gating, but a robust gating deficit in SII, supporting the presence of cross modal gating deficits in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
25J. Chem. Neuroanat. 2008 Mar 35: 179-87
PMID18061401
TitlePostweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis.
AbstractNeonatal ventral hippocampal (nVH) leSIons in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nVH-leSIons result in SIgnificant decreases in both length of dendrites and dendritic denSIty of spines of pyramidal neurons of the prefrontal cortex (PFC) and in the denSIty of dendritic spines of medium spiny neurons of the nucleus accumbens (NAcc). Moreover, postweaning social isolation induces major decreases in dendritic spiny denSIty of PFC neurons. We investigated here the comparative dendritic morphology of PFC pyramidal neurons and NAcc medium spiny neurons in nVH rats, following social isolation after weaning (8 weeks). Morphological characteristics of dendrites were measured uSIng the Golgi-Cox procedure followed by a Sholl analySIs. Social isolation (SI) by itself induced decreases in dendritic length and dendritic spine denSIty of the NAcc. In socially isolated nVH-leSIon rats decrease in dendritic length in PFC and NAcc neurons were exacerbated whereas an increase in spine denSIty of medium spiny neurons was observed in the NAcc. These results indicate that nVH-leSIons alter dendritic morphology of NAcc and PFC neurons. These anatomical modifications in both structures may be relevant to behaviors observed in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
26J Psychiatr Res 2008 Oct 42: 1076-85
PMID18295798
TitleEthnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia.
AbstractAtypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown.
We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adipoSIty by DEXA, (2) visceral adipoSIty by abdominal CT, and (3) insulin senSItivity (SI) and (4) pancreatic function ("dispoSItion index", DI) by intravenous glucose tolerance test.
At baseline, groups (risperidone: n=28; olanzapine: n=31) were overweight or obese by body mass index (risperidone: 28.4+/-5.4, olanzapine: 30.6+/-7.0kg/m2). Both drugs induced weight gain (p<0.004). Total adipoSIty was increased by olanzapine at 6 weeks (p=0.0006) and by both treatments at 24 weeks (p<0.003). Visceral adipoSIty was increased by olanzapine and risperidone by 24 weeks (p<0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adipoSIty and S(I), we performed secondary analySIs in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adipoSIty (p<0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p=0.033), indicating inadequate pancreatic compensation for insulin reSIstance.
This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
27J Psychiatr Res 2009 Mar 43: 607-14
PMID18951556
TitleCerebral network deficits in post-acute catatonic schizophrenic patients measured by fMRI.
AbstractTwelve patients with catatonic schizophrenia and 12 matched healthy controls were examined with functional MRI while performing a motor task. The aim of our study was to identify the intracerebral pathophySIological correlates of motor symptoms in catatonic patients. The motor task included three conditions: a self-initiated (SI), an externally triggered (ET) and a rest condition. Statistical analySIs was performed with SPM5. During the self-initiated movements patients showed SIgnificantly less activation than healthy controls in the supplementary motor area (SMA), the prefrontal and parietal cortex. Our results suggest a dysfunction of the "medial motor system" in catatonic patients. Self-initiated and externally triggered movements are mediated by different motor loops. The "medial loop" includes the SMA, thalamus and basal ganglia, and is necessary for self-initiated movements. The "lateral loop" includes parts of the cerebellum, lateral premotor cortex, thalamus and parietal association areas. It is involved in the execution of externally triggered movements. Our findings are in agreement with earlier behavioral data, which show deficits in self-initiated movements in catatonic patients but no impairment of externally triggered movements.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
28J Psychiatr Res 2009 Mar 43: 607-14
PMID18951556
TitleCerebral network deficits in post-acute catatonic schizophrenic patients measured by fMRI.
AbstractTwelve patients with catatonic schizophrenia and 12 matched healthy controls were examined with functional MRI while performing a motor task. The aim of our study was to identify the intracerebral pathophySIological correlates of motor symptoms in catatonic patients. The motor task included three conditions: a self-initiated (SI), an externally triggered (ET) and a rest condition. Statistical analySIs was performed with SPM5. During the self-initiated movements patients showed SIgnificantly less activation than healthy controls in the supplementary motor area (SMA), the prefrontal and parietal cortex. Our results suggest a dysfunction of the "medial motor system" in catatonic patients. Self-initiated and externally triggered movements are mediated by different motor loops. The "medial loop" includes the SMA, thalamus and basal ganglia, and is necessary for self-initiated movements. The "lateral loop" includes parts of the cerebellum, lateral premotor cortex, thalamus and parietal association areas. It is involved in the execution of externally triggered movements. Our findings are in agreement with earlier behavioral data, which show deficits in self-initiated movements in catatonic patients but no impairment of externally triggered movements.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
29Behav. Brain Res. 2009 Aug 202: 114-21
PMID19447287
TitleBehavioral abnormality and pharmacologic response in social isolation-reared mice.
AbstractSocial isolation (SI) rearing in rodents causes a variety of behavioral changes, including hyperlocomotion, anxiety, impulSIvity, aggresSIon, and learning and memory deficits. These behavioral abnormalities in rodents may be related to the symptoms in patients with neuropsychiatric disorders, such as attention-deficit hyperactivity disorder, obsesSIve-compulSIve disorder, autism, schizophrenia and depresSIon. In this study, we examined the effect of long-term SI rearing after weaning on emotional behaviors and cognitive function in mice. Furthermore, the effects of methylphenidate (MPH), clozapine (CLZ) and fluoxetine (FLX) on SI-induced behavioral changes were examined to measure the predictive validity of SI-reared mice as an animal model for these neuropsychiatric disorders. MPH improved SI-induced anxiety-like behavior in the elevated-plus maze test, but had no effect on aggresSIve behavior. In contrast, CLZ ameliorated aggresSIve behavior, but not anxiety-like behavior in SI-reared mice. Repeated FLX treatment prevented SI-induced aggresSIve behavior and social interaction deficits. These findings suggest that SI-induced behavioral abnormality is a psychobehavioral complex relevant to various clinical symptoms observed in neuropsychiatric disorders and that SI-reared mice are a useful animal model to study the pathophySIology/pathogeneSIs of these diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
30PLoS ONE 2009 -1 4: e4227
PMID19156216
TitleThe 5-choice continuous performance test: evidence for a translational test of vigilance for mice.
AbstractAttentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications deSIgned to improve cognition in schizophrenia. Although vigilance is assessed frequently uSIng the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.
We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-SIgnal trials, thus mimicking task parameters of human CPTs that use SIgnal and non-SIgnal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a SImple reaction-time (RT) task involving only one choice (1CRT task). We hypotheSIzed that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the senSItivity index measure from SIgnal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).
C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, conSIstent with human performance in SImple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
31Acta Psychiatr Scand 2009 Jun 119: 457-65
PMID19183127
TitleA double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia.
AbstractThe primary purpose of this 8-week double-blind, placebo-controlled trial of roSIglitazone 4 mg/day was to examine its effect on insulin senSItivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin reSIstance.
Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI.
Controlling for the baseline, comparing the roSIglitazone group with placebo group, there was a non-SIgnificant improvement in SG (0.016 +/- 0.006-0.018 +/- 0.008, effect SIze = 0.23, P = 0.05) with a trend of improvement in SI in the roSIglitazone group (4.6 +/- 2.8-7.8 +/- 6.7, effect SIze = 0.18, P = 0.08). There was a SIgnificant reduction in small low-denSIty lipoprotein cholesterol (LDL-C) particle number (987 +/- 443-694 +/- 415, effect SIze = 0.30, P = 0.04).
RoSIglitazone may have a role in addresSIng insulin reSIstance and lipid abnormalities associated with clozapine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
32Psychiatry Res 2009 Oct 174: 24-31
PMID19796920
TitleEvidence for reduced somatosensory lateralisation and focalisation in schizophrenia.
AbstractNeuroimaging studies indicate diminished lateralisation of cerebral activity during motor tasks and language procesSIng in schizophrenia. Some evidence also indicates that decreased lateralisation is accompanied by more diffuse intra-hemispheric activation, suggesting that diminished lateralisation might be part of a more general diminution of regional functional specialisation. In the case of pasSIve procesSIng of elementary somatosensory stimuli, evidence for decreased lateralisation derived from event-related potential studies, is conflicting. The greater spatial resolution of functional magnetic resonance imaging (fMRI) offers the potential to resolve this conflict. We report an fMRI study of 22 right-handed individuals with schizophrenia, 21 right-handed healthy individuals and 10 non-right-handed healthy individuals, deSIgned to test the hypotheSIs that in schizophrenia there is a diminution of both lateralisation and intra-hemispheric focalisation during the pasSIve procesSIng of vibrotactile stimuli delivered to the right index finger. SIgnificantly reduced lateralisation of activity in primary somatosensory cortex (SI) was observed in the schizophrenia group as compared to the healthy right-handed group. There was a trend for a reduction in SI lateralisation in the schizophrenia group compared to the healthy non-right-handed group. Contralateral SI focalisation was also SIgnificantly reduced in the schizophrenia group compared to both healthy groups. SI focalisation was negatively correlated with severity of disorganisation symptoms in the schizophrenia group. These results support the hypotheSIs that a generalised loss of functional specialisation is fundamental to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
33J Psychiatr Pract 2009 Jul 15: 251-61
PMID19625881
TitleWaist circumference is the best anthropometric predictor for insulin resistance in nondiabetic patients with schizophrenia treated with clozapine but not olanzapine.
AbstractThe goal of this study was to evaluate which anthropometric measure (human body measurement) best predicts insulin reSIstance measured by the insulin senSItivity index (SI) and the homeostaSIs model of assessment of insulin reSIstance (HOMA-IR) in nondiabetic patients with schizophrenia treated with clozapine or olanzapine.
We conducted a cross-sectional study of nondiabetic subjects with schizophrenia being treated with olanzapine or clozapine uSIng a frequently sampled intravenous glucose tolerance test, nutritional assessment, and anthropometric measures, to assess the relationship between anthropometric measures and insulin reSIstance.
No difference was found between the groups treated with clozapine and olanzapine in age, gender, race, body mass index (BMI), waist circumference (WC), lipid levels, HOMA-IR, or SI. The dispoSItion index (SI x the acute insulin response to glucose), which measures how the body compensates for insulin reSIstance to maintain a normal glucose level, was SIgnificantly lower in the group treated with clozapine than in the group treated with olanzapine (1067+/-1390 vs. 2521+/-2805; P=0.013), suggesting that the subjects treated with clozapine had a reduced compensatory response to IR compared with the subjects treated with olanzapine. In the clozapine group, both higher WC and BMI were SIgnificantly associated with elevated HOMA-IR and lower SI; however, WC was a stronger correlate of IR than BMI, as measured by SI (-0.50 vs. -0.40). In the olanzapine group, neither WC nor BMI was SIgnificantly associated with any measure of glucose metabolism.
In this study, WC was the SIngle best anthropometric surrogate for predicting IR in patients treated with clozapine but not olanzapine. The results suggest that WC may be a valuable screening tool for predicting IR in patients with schizophrenia being treated with clozapine who are at relatively higher risk of developing the metabolic syndrome, type 2 diabetes mellitus, and associated cardiovascular disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
34ORL J. Otorhinolaryngol. Relat. Spec. 2010 -1 72: 235-41
PMID20689336
TitlePsychological aspects of female patients with moderate-to-severe persistent allergic rhinitis.
AbstractAllergic rhinitis (AR) has been shown to impair social life and psychological functioning. The objective of our study was to explore the relationships between moderate-to-severe perSIstent AR and personality traits in non-psychiatric female outpatients.
Female subjects were asSIgned to the allergic (n = 52, 24 SIngletons and 28 non-SIngletons) or non-allergic group (n = 28, 11 SIngletons and 17 non-SIngletons) on the baSIs of skin prick tests (SPT) and allergic symptoms. Individuals in this study were only allergic to Dermatophagoides pteronysSInus and/or D. farinae. The psychological aspects of the female subjects were assessed by uSIng the Minnesota MultiphaSIc Personality Inventory (MMPI).
The allergic group scored SIgnificantly higher than the non-allergic group on 6 clinical scales [hypochondriaSIs (Hs), depresSIon (D), hysteria (Hy), psychasthenia (Pt), schizophrenia (Sc), social introverSIon (SI)] and 1 validity scale [infrequency (F)]. AnalySIs of female SIngleton outpatient MMPI profiles showed that allergic subjects scored SIgnificantly higher on D, Hy, masculinity/femininity (Mf), Pt, and F. In addition, the grade of skin index (resulting from an SPT) was poSItively correlated with T-scores on the Hs, Hy, Pt, and Sc scales.
Women with moderate-to-severe perSIstent AR, especially SIngleton patients, show poorer psychological functioning, indicating the close relationship between moderate-to-severe perSIstent AR and psychological functioning.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
35Psychopharmacology (Berl.) 2010 Aug 211: 355-66
PMID20552172
TitleOpposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia.
AbstractRepeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progresSIvely increases non-regulatory water intake. This effect may model psychotic polydipSIa, a potentially fatal but poorly understood condition.
The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model.
Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist haloperidol (Hal) prior to QNP treatment. A group of rats SImilarly treated was also assessed for orexin A (OxA) expresSIon in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipSIa was evaluated.
In rats made polydipSIc by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. Hal 0.2 mg/kg prevented both polydipSIa and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a Hal-reverSIble way, OxA expresSIon in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipSIa.
Results disclose compulSIve components in QNP-induced polydipSIa that are mediated by dopamine D2 receptors. QNP also regulates OxA expresSIon in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipSIa. We suggest that dopamine and OxA play oppoSIte roles in QNP-induced polydipSIa.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
36Psychopharmacology (Berl.) 2010 Aug 211: 277-89
PMID20571781
TitleA follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice.
AbstractHeavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (Nrg1 HET) mice are more senSItive to some effects of the psychotropic cannabis constituent Delta(9)-tetrahydrocannabinol (THC). We report data from a follow-up study in female Nrg1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia.
Mice were injected with THC (0, 5 or 10 mg/kg i.p.) 30 min before a test battery: open field, elevated plus maze, novel object recognition (set 1) or light-dark, social interaction (SI) and prepulse inhibition (PPI 1: variable interstimulus interval (ISI); set 2). Another set (set 3) was injected with the same doses of THC before a fixed interstimulus interval PPI test (PPI 2).
Female Nrg1 HETs displayed the hallmark increased locomotor activity at 5 months and anxiolytic-like behaviour in the open field at 3 and 5 months. THC decreased locomotor activity in both genotypes. THC selectively reduced some SI behaviours in WT mice. Baseline PPI was enhanced in mutants under a variable ISI, while THC had no effect on PPI uSIng either protocol.
This study reports novel findings on the baseline PPI profile and reSIstance to THC-induced social withdrawal in female Nrg1 HET mice. This is the first description of THC effects in females of this mouse model and suggests that the transmembrane domain Nrg1 mutation does not appear to have a severe impact on the behavioural senSItivity to THC in female mice.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
37Psychiatry Res 2010 Apr 176: 132-6
PMID20202691
TitleCortical motor neurophysiology of patients with schizophrenia: a study using transcranial magnetic stimulation.
AbstractTrancranial magnetic stimulation (TMS) provides a non-invaSIve means for exploring phySIological alterations of central motor control in a variety of neuropsychiatric diseases. The present study aimed to assess the neurophySIological profile of muscle evoked responses to a standard TMS procedure in 51 medicated patients with schizophrenia and 51 age- and sex-matched healthy subjects. Motor evoked potentials (MEPs) from the abductor pollicis brevis muscle were elicited by stimulation of the contralateral motor cortex with a circular coil. The hot spot was marked, and the resting motor threshold (RMTh), the stimulus intenSIty for maximum MEP (SI-max), the post-stimulus SIlent period of voluntary muscle activity, and MEP latency and amplitude were measured. The main findings were the SIgnificantly higher than normal values for RMTh and SI-max, which are both indices of neuronal excitability. In particular, patients who had zipraSIdone in their therapeutic regimen demonstrated the highest SI-max for both hemispheres, and the highest RMTh for the left hemisphere, patients receiving olanzapine demonstrated the lowest RMTh for the left hemisphere, and those on quetiapine showed intermediate values. The SIlent period was longer in the patients than in the controls when a RMTh-related SI was used and did not differ between the two groups when a fixed SI was used. We concluded that the observed TMS changes could be interpreted as primary alterations of intracortical motor excitability followed by defects of cortical inhibition and should be attributed to schizophrenia, antipsychotic medication or the interaction between the two factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
38Early Interv Psychiatry 2010 Nov 4: 270-4
PMID20977682
TitleNaming psychosis: the Hong Kong experience.
Abstractschizophrenia translates in Chinese as 'Mind Split Disease' which is heavily stigmatizing. The narrow conceptualization for schizophrenia alone was insufficient, in the context of early detection and intervention for psychoSIs. The need for an effective Chinese translation for psychotic disorders was imminent upon the launch of the Early Assessment Service for Young People with PsychoSIs in Hong Kong, where public awareness strategies had to be built upon effective communication of the disorder.
'SI Jue Shi Tiao', the new term for psychoSIs, described 'thought and perceptual dysregulation'. This new terminology and concept was strategically introduced to the local community.
The term 'SI Jue Shi Tiao' was taken up well locally and had demonstrated interactions within the Chinese and East ASIan communities. The public has taken in the broader concept of psychoSIs, in contrary to the previous concept of schizophrenia per se.
In Hong Kong, the restrictive view of perceiving psychotic disorders as schizophrenia was broadened upon the introduction of a more embracing, less stigmatizing term 'SI Jue Shi Tiao'. Effective establishment of this term to the local vocabulary allowed a baSIs for communication as well as public education work. Further evaluation is necessary to determine the effectiveness of the naming and to guide further public awareness strategies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
39Ann Clin Psychiatry 2010 Feb 22: 33-42
PMID20196981
TitleDietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone.
AbstractHigh dietary saturated fat (SF) intake is strongly linked to metabolic disturbances. The goal of this study was to understand the relationship between clozapine and risperidone with glucose and lipid metabolism and dietary fat intake in patients with schizophrenia.
Thirty-one clozapine-treated patients and 15 risperidone-treated patients were assessed uSIng a 4-day dietary record, an IV glucose tolerance test, and lipid profiles.
Clozapine-treated patients consumed a SIgnificantly higher percentage of SF than did risperidone-treated patients (13.7% +/- 3.4% vs 10.6% +/- 3.0 % of total energy; P = .007). Compared with the risperidone group, the clozapine group also had a SIgnificantly higher percentage of total fat in their diet (36% +/- 6.7% vs 30.9% +/- 5.7% of total energy; P = .007). SImilarly, the clozapine group had a SIgnificant impairment in insulin senSItivity index (SI), glucose effectiveness (SG), and dispoSItion index (DI) compared with the risperidone group (P < .05). Pearson correlation analySIs of both groups showed that dietary SF was SIgnificantly correlated with impairment in glucose homeostaSIs (SG: r = -0.43; P = .004; DI: r = -0.35; P = .02).
Abnormal glucose homeostaSIs in atypical clozapine-treated patients with schizophrenia may be associated with or aggravated by high dietary SF consumption.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
40Pharmacol. Biochem. Behav. 2010 Mar 95: 72-9
PMID20035782
TitlePost-weaning social isolation increases activity in a novel environment but decreases defensive burying and subchronic MK-801 enhances the activity but not the burying effect in rats.
AbstractSubchronic treatment with a non-competitive glutamate NMDA-receptor antagonist [e.g., MK-801 or phencyclidine] or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produce deficits SImilar to some of the poSItive and negative symptoms of schizophrenia. Few studies have evaluated the effects of these treatments on emotional behavior. We hypotheSIzed that subchronic MK-801, post-weaning SI or the two in combination would alter activity in a novel environment, anxiety-like behaviors in the elevated plus-maze, coping responses in the defenSIve burying paradigm and social behavior. In experiment 1, SI rats (n=17) showed increased locomotor activity when exposed to a novel environment, no change in plus-maze behavior and decreased defenSIve burying when compared to group housed rats (n=16). Subchronic MK-801 enhanced the increase in activity but not the decrease in burying in SI rats. Experiment 2 evaluated the effects on social behavior of post-weaning SI. The locomotor and burying results of experiment 1 were replicated and SI rats (n=9) were found to decrease orientation towards a novel conspecific social target when compared to group housed rats (n=8). The behavioral abnormalities of SI rats may be a manifestation of GABAergic dysfunction that has recently become evident in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
41Front Behav Neurosci 2011 -1 5: 31
PMID21747763
TitleRecovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs.
AbstractRecent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine posSIble effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for 5?weeks then returned to normal food for 3?weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze (EPM), social interaction (SI), and Y-maze test. EPM performance recovered to normal range within 2?weeks after CPZ withdrawal. Alterations in SI showed no recovery. Antipsychotics did not alter animals' behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, SIgnificantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs SIgnificantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and SI deficit may be reSIstant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that poSItive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
42Front Behav Neurosci 2011 -1 5: 31
PMID21747763
TitleRecovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs.
AbstractRecent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine posSIble effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for 5?weeks then returned to normal food for 3?weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze (EPM), social interaction (SI), and Y-maze test. EPM performance recovered to normal range within 2?weeks after CPZ withdrawal. Alterations in SI showed no recovery. Antipsychotics did not alter animals' behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, SIgnificantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs SIgnificantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and SI deficit may be reSIstant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that poSItive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
43Psychopharmacology (Berl.) 2011 May 215: 257-66
PMID21193984
TitlePharmacological characterization of social isolation-induced hyperactivity.
AbstractSocial isolation (SI) of rats directly after weaning is a non-pharmacological, non-leSIon animal model based on the neurodevelopmental hypotheSIs of schizophrenia. The model causes several neurobiological and behavioral alterations conSIstent with observations in schizophrenia.
In the present study, we evaluated if isolated rats display both a pre-pulse inhibition (PPI) deficit and hyperactivity. Furthermore, the senSItivity of SI hyperactivity to antipsychotic was evaluated.
Rats were socially isolated or group-housed for 12 weeks starting on postnatal day 25. In one batch of animals, the PPI and hyperactivity response were repeatedly compared. Furthermore, we investigated the robustness of the SI-induced hyperactivity by testing close to 50 batches of socially isolated or group-housed rats and tested the senSItivity of the assay to first- and second-generation antipsychotics, haloperidol, olanzapine, and risperidone, as well as the group II selective metabotrobic glutamate receptor agonist (LY404039).
Socially isolated rats showed a minor PPI deficit and a robust increase in hyperactivity compared with controls. Furthermore, SI-induced hyperactivity was selectively reversed by all antipsychotics, as well as the potential new antipsychotic, LY404039.
SI-induced hyperactivity was more pronounced and robust, as compared with SI-induced PPI deficits. Furthermore, SI-induced hyperactivity might be predictive for antipsychotic efficacy, as current treatment was effective in the model. Finally, uSIng LY404039, a compound in development against schizophrenia, we have shown that the hyperactivity assay is senSItive to potential novel mechanisms of action. Thus, SI-induced hyperactivity might be a robust and novel in vivo screening assay of antipsychotic efficacy.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
44Schizophr Bull 2011 Sep 37: 1048-56
PMID20185539
TitleThe effect of context processing on different aspects of social cognition in schizophrenia.
AbstractIt is well known that individuals with schizophrenia have impaired social cognition. The construct of social cognition involves several components, including perception, interpretation, and the ability to integrate context (Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol. 2001;11:231-239; Brothers L. The social brain: a project for integrating primate behavior and neurophySIology in a new domain. Concepts Neurosci. 1990;1:27-61). Importantly, a number of studies have suggested that deficits in context procesSIng underlie cognitive dysfunction in schizophrenia (Penn DL, Corrigan PW, Bentall RP, Racenstein JM, Newman L. Social cognition in schizophrenia. Psychol Bull. 1997;121(1):114-132; Green MF, Nuechterlein KH. Should schizophrenia be treated as a neurocognitive disorder? Schizophr Bull. 1999;25:309-319). Thus, the purpose of the current study was to investigate the relationship between context procesSIng and different aspects of social cognition in schizophrenia.
Individuals with schizophrenia (n = 41) and the healthy controls (n = 32) participated in this study. The participants completed 2 sections of The Awareness of Social Inference Test: (1) social inference minimal (SI-M) and (2) social inference enriched (SI-E). They also completed face and voice emotion discrimination tasks. In addition, we used the AX-Continuous Performance Test (AX-CPT) to measure context procesSIng and the n-back task to measure working memory more generally.
AX-CPT performance in schizophrenia was poSItively correlated with both SI-M and SI-E performance but not with either the face or the voice discrimination. Furthermore, the correlation between AX-CPT performance and SI-M/SI-E performance was SIgnificantly stronger in individuals with schizophrenia than in controls.
These results suggest that impairments in context procesSIng are related to inferential components of social cognition in schizophrenia but not to the ability to recognition facial or vocal emotion. As such, deficits in context procesSIng may contribute to deficits in both "hot" and "cold" aspects of cognition in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
45Pharmacol. Biochem. Behav. 2012 Jul 102: 109-17
PMID22503968
TitleThe antidepressant phenelzine enhances memory in the double Y-maze and increases GABA levels in the hippocampus and frontal cortex of rats.
AbstractSubchronic treatment with a non-competitive glutamate NMDA-receptor antagonist (e.g., MK-801, phencyclidine) or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produces deficits SImilar to some poSItive and negative symptoms of schizophrenia. Down-regulation of GABA-ergic neurons has been demonstrated in people with schizophrenia and treatment with GABA-ergic compounds (including benzodiazepines, valproate) has shown some favorable outcomes. We hypotheSIzed that subchronic MK-801 (0.5 mg/kg 2 times daily for 7 days), post-weaning SI or the two in combination will alter activity in a novel environment and memory in the double Y-maze (a test with a spatial discrimination and spatial alternation component) and that treatment with phenelzine (PLZ), a monoamine oxidase (MAO)-inhibiting antidepressant that also produces a rapid increase in brain levels of GABA, will improve memory. SI rats (n=18) showed increased locomotor activity when exposed to a novel environment but no deficits in the double Y-maze and the combination of SI plus subchronic MK-801 did not alter these effects. Delays did not affect performance in the spatial discrimination component of the Y-maze and decreased performance in the alternation component for saline rats but not MK-801 rats. Treatment with PLZ improved performance in both components of the Y-maze in a dose-dependent manner. Neurochemical analyses confirmed that PLZ increased GABA levels in the brain and changes in levels of dopamine, serotonin and their metabolites were conSIstent with inhibition of MAO. It was concluded that PLZ does not specifically augment memory in SI or subchronic MK-801-treated rats.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
46Pharmacol. Biochem. Behav. 2012 Apr 101: 231-8
PMID22293110
TitlePost-weaning social isolation and subchronic NMDA glutamate receptor blockade: effects on locomotor activity and GABA signaling in the rat suggest independent mechanisms.
AbstractAnimal models of schizophrenia symptoms include administration of noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, such as MK-801, and post-weaning social isolation (SI). We tested the hypotheSIs that a "double-hit" model, in which MK-801 administration during adulthood [post-natal day (P) 56-62] and SI are combined, produces greater behavioral and neurochemical effects than either insult alone. Rats obtained at weaning (P21) were either SI (n=21) or group housed (n=16) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg i.p., 2 times daily for 7 days) or saline injections from P56-62. At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess GAT-1 activity and GABA(A) receptor expresSIon in the frontal cortex and hippocampus. SI resulted in increased locomotor activity, GAT-1 activity in frontal cortex and hippocampus and GABA(A) receptor expresSIon in the frontal cortex; MK-801 increased GABA(A) receptor expresSIon in the hippocampus. Activity changes were correlated with changes in hippocampal GAT-1 and frontocortical GABA(A) receptor number. There was no evidence that the double-hit produced a greater effect. Increased GAT-1 activity may be associated with suppresSIon of GABA-mediated inhibitory synaptic transmisSIon and increased GABA(A) receptor expresSIon may be a compensatory response to decreased availability of GABA. Results suggest that SI and subchronic MK-801 may act through independent mechanisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
47Mol. Psychiatry 2013 Dec 18: 1249-64
PMID23958961
TitleDiscovery and validation of blood biomarkers for suicidality.
AbstractSuicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and poSItive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychoSIs, we decided to identify blood gene expresSIon biomarkers for suicidality, looking at differential expresSIon of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states uSIng a powerful intrasubject deSIgn, as well as an intersubject case-case deSIgn, to generate a list of differentially expressed genes. Second, we used a comprehenSIve Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a BayeSIan strategy for identifying and prioritizing findings, reducing the false-poSItives and false-negatives inherent in each individual approach. Third, we examined whether expresSIon levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner's office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise SIgnificant change from no SI to high SI states, and then to the suicide completers group. SIx out of them (15%) remained SIgnificant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a SImilar but weaker pattern in a live cohort of psychoSIs (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tenSIn homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the SIx biomarkers that survived Bonferroni correction showed SImilar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimenSIonal approach uSIng SAT1 blood expresSIon levels and two SImple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this SImple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptoSIs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
48J Affect Disord 2013 Jul 149: 291-8
PMID23531358
TitlePrevalence and correlates of suicidal ideation among Operation Enduring Freedom and Operation Iraqi Freedom veterans.
AbstractWe sought to determine the prevalence and correlates of suicidal ideation (SI) among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans following the Department of Veterans Affairs' (VA) 2007 implementation of required brief SI assessments for veterans who screen poSItive for depresSIon and post-traumatic stress disorder.
We retrospectively identified OEF/OIF veterans screened for depresSIon uSIng the Patient Health Questionnaire (PHQ-2) between April 2008 and September 2009 at three geographically-distinct VA Medical Centers' primary care or mental health clinics. Veteran responses to a two-item risk assessment tool (VA Pocket Card) or PHQ-9 9th item, administered following a poSItive depresSIon screen (PHQ-2?3), were determined uSIng manual chart review. Generalized estimating equations were used to calculate adjusted odds ratios for demographic and clinical correlates of poSItive SI assessments.
Of 1340 OEF/OIF veterans with poSItive depresSIon screens, 32.4% reported SI. In multivariate models, odds of SI were lower for non-Hispanic white veterans (AOR=0.68) and greater for those with PHQ-2?5 (AOR=1.87), depresSIon (AOR=1.45), bipolar disorder/schizophrenia (AOR=2.84), and 2 or ?3 diagnoses (AORs=1.59 and 2.49, respectively).
Study findings may not be generalizable to non-veteran patient populations and the study does not address the reliability and validity of tools employed for brief suicidal ideation assessment.
SI is common among OEF/OIF veterans who receive VA care, perhaps more so among non-white veterans. Targeting veterans with higher PHQ-2 scores for SI assessment should be conSIdered to reduce patient and administrative burden.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
49J Child Adolesc Psychopharmacol 2013 Feb 23: 49-53
PMID23410141
TitleSuicidal thoughts are associated with platelet counts in adolescent inpatients.
AbstractPlatelets (PLT), which serve as the primary hemostatic indicator, can be used as a peripheral model for studying monoamine turnover in the brain. Therefore, they are attractive targets as circulatory biomarkers for the detection of psychiatric disorders. However, PLT counts have not been utilized as a peripheral biomarker of psychopathology.
This study was a retrospective analySIs of PLT counts upon admisSIon of 108drug-nave adolescents hospitalized in an inpatient psychiatric department. PLT counts of patients with suicidal ideation (SI) were compared with those of nonsuicidal in patients (NSI) and those of 77 healthy adolescents, serving as a control group. The patients' disorders were diagnosed and clasSIfied by one of four American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM IV) diagnoses, that is, unipolar depresSIon, bipolar depresSIon, schizophrenia, and a pooled group of conduct and borderline personality disorders.
SIgnificantly higher PLT counts were observed in SI patients, as compared with NSI patients (300,20053.3/mL vs. 253,90053.2/mL, respectively; p=0.0001). A SIgnificant difference in PLT counts in SI patients, relative to the control group, was also noted (300,20053.3/mL vs. 254,00052/mL, respectively; p=<10(-26)). Finally, a SIgnificant difference in PLT counts was observed between conduct/borderline personality disorders patient with and without suicidal ideation (292,00055/mL vs. 246,00064/mL, respectively; p=0.001).
PLT counts are higher in suicidal hospitalized adolescents than in nonsuicidal inpatients, as well as than in controls.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
50J. Neurochem. 2013 Feb 124: 548-57
PMID23083323
TitleDifferential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.
AbstractDecreased parvalbumin expresSIon is a hallmark of the pathophySIology of schizophrenia and has been associated with abnormal cognitive procesSIng and decreased network specificity. It is not known whether this decrease is due to reduced expresSIon of the parvalbumin protein or degeneration of parvalbumin-poSItive interneurons (PV(+) interneurons). In this study, we examined PV(+) expresSIon in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. USIng a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically SIgnificant reduction in the number of PV(+) interneurons (p=0.021) and glial cells (p=0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expresSIon or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expresSIon below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
51Schizophr Bull 2013 Jul 39: 820-9
PMID22892556
TitleCortex morphology in first-episode psychosis patients with neurological soft signs.
Abstractschizophrenia is a complex brain disorder associated with numerous etiological factors and pathophySIological pathways leading to multiple clinical outcomes. Compelling evidence suggests that deviations in neurodevelopmental processes are a major risk factor of schizophrenia. The identification of patients with high neurodevelopmental deviance is an important issue as it could help to identify homogeneous subgroups of patients with SImilar pathophySIological pathways, a key step to decipher the etiology of this complex condition. Several clinical arguments suggest that schizophrenia patients with Neurological Soft SIgns (NSS)--ie, observable defects in motor coordination, motor integration, and sensory integration--would have high neurodevelopmental deviance. Based on the analySIs of magnetic resonance imaging of 44 first-episode psychoSIs patients, we compared the cortex morphology, a marker of brain development, in patients with NSS vs patients with nonSIgnificant NSS. The cortex morphology was automatically assessed from three-dimenSIonal global sulcal index (g-SI, the ratio between total sulcal area and outer cortex area) and regional sulcal indexes (r-SI, the ratio between the area of pooled labeled sulci and the total outer cortex area). Patients with NSS were found to have a lower g-SI in both hemispheres and a lower r-SI in left dorsolateral prefrontal and right lateral occipital cortices. Exploratory analyses revealed correlations between NSS dimenSIons and r-SI in distinct cortical areas, including dorsolateral and medial prefrontal cortices, lateral temporal, occipital, superior parietal, and medial parieto-occipital cortices. These findings provide evidence of distinct neurodevelopmental pathways in patients with NSS as compared with patients with nonSIgnificant NSS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
52Behav. Brain Res. 2014 Jun 266: 85-93
PMID24613239
TitleAuditory sensory processing deficits in sensory gating and mismatch negativity-like responses in the social isolation rat model of schizophrenia.
AbstractPatients with schizophrenia exhibit disturbances in information procesSIng. These disturbances can be investigated with different paradigms of auditory event related potentials (ERP), such as sensory gating in a double click paradigm (P50 suppresSIon) and the mismatch negativity (MMN) component in an auditory oddball paradigm. The aim of the current study was to test if rats subjected to social isolation, which is believed to induce some changes that mimic features of schizophrenia, displays alterations in sensory gating and MMN-like response. Male Lister-Hooded rats were separated into two groups; one group socially isolated (SI) for 8 weeks and one group housed (GH). Both groups were then tested in a double click sensory gating paradigm and an auditory oddball paradigm (MMN-like) paradigm. It was observed that the SI animals showed reduced sensory gating of the cortical N1 amplitude. Furthermore, the SI animals showed SIgnificant reduction in cortical MMN-like response compared with the GH animals. No deficits in sensory gating or MMN-like response were observed in the hippocampus (CA3) of the SI animals compared with GH animals. In concluSIon, the change in sensory gating of the N1 amplitude supports previous findings in SI rats and the reduced MMN-like response is SImilar to the deficits of MMN seen in patients with schizophrenia. SInce reduced auditory MMN amplitude is believed to be more selectively associated with schizophrenia than other measures of sensory gating deficits, the current study supports the face validity of the SI reared rat model for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
53Neurosci. Lett. 2014 Oct 582: 125-9
PMID25218712
TitleSocial interaction of rats is related with baseline prepulse inhibition level.
AbstractThe symptoms of schizophrenia are evaluated in three general categories: poSItive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model poSItive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by uSIng a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively asSIgned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was asSIgned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a SIgnificant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were SIgnificantly lower, and the average distance between rat pairs was SIgnificantly longer than HI rats. In the EPM test LI and HI rats showed SImilar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
54PLoS ONE 2014 -1 9: e91228
PMID24603990
TitleSplitting in schizophrenia and borderline personality disorder.
AbstractSplitting describes fragmentation of conscious experience that may occur in various psychiatric disorders. A purpose of this study is to examine relationships between psychological process of splitting and disturbed cognitive and affective functions in schizophrenia and borderline personality disorder (BPD).
In the clinical study, we have assessed 30 patients with schizophrenia and 35 patients with BPD. The symptoms of splitting were measured uSIng self-reported Splitting Index (SI). As a measure of semantic memory disorganization we have used verbal fluency test. Other psychopathological symptoms were assessed uSIng Health of the Nation Outcome Scale (HoNOS).
Main results show that SI is SIgnificantly higher in BPD group than in schizophrenia, and on the other hand, verbal fluency is SIgnificantly lower in schizophrenia group. Psychopathological symptoms measured by HoNOS are SIgnificantly higher in the BPD group than in schizophrenia. SIgnificant relationship was found between verbal fluency and the SI "factor of others" (Spearman r?=?-0.52, p<0.01) in schizophrenia patients.
Processes of splitting are different in schizophrenia and BPD. In BPD patients splitting results to mental instability, whereas in schizophrenia the mental fragmentation leads to splitting of associations observed as lower scores of verbal fluency, which in principle is in agreement with Bleuler's historical concept of splitting in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
55J Psychiatr Res 2014 Aug 55: 117-25
PMID24793538
TitleGender-related differences in the associations between sexual impulsivity and psychiatric disorders.
AbstractSexual impulSIvity (SI) has been associated with conditions that have substantial public health costs, such as sexually transmitted infections and unintended pregnancies. However, SI has not been examined systematically with respect to its relationships to psychopathology. We aimed to investigate associations between SI and psychopathology, including gender-related differences.
We performed a secondary data analySIs of Wave-2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a national sample of 34,653 adults in the United States. DSM-IV-based diagnoses of mood, anxiety, drug and personality disorders were assessed uSIng the Alcohol Use Disorder and Associated Disabilities Interview Scheduled DSM-IV VerSIon.
The prevalence of SI was conSIderable (14.7%), with greater acknowledgment by men than women (18.9% versus 10.9%; p<0.0001). For both women and men, SI was poSItively associated with most Axis-I and Axis-II psychiatric disorders (OR range: Women, Axis-I:1.89-6.14, Axis-II:2.10-10.02; Men, Axis-I:1.92-6.21, Axis-II:1.63-6.05). SIgnificant gender-related differences were observed. Among women as compared to men, SI was more strongly associated with social phobia, alcohol abuse/dependence, and paranoid, schizotypal, antisocial, borderline, narcisSIstic, avoidant and obsesSIve-compulSIve personality disorders.
The robust associations between SI and psychopathology across genders suggest the need for screening and interventions related to SI for individuals with psychiatric concerns. The stronger associations between SI and psychopathology among women as compared to men emphaSIze the importance of a gender-oriented perspective in targeting SI. Longitudinal studies are needed to determine the extent to SI predates, postdates or co-occurs with specific psychiatric conditions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
56Brain Res. 2015 Dec -1: -1
PMID26723568
TitleFate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells.
AbstractCortical GABAergic interneurons modulate cortical excitation, and their dysfunction is implicated in a multitude of neuropsychiatric disorders including autism, schizophrenia and epilepsy. Consequently, the study of cortical interneuron development, and their derivation from stem cells for transplantation therapy, has garnered intense scientific interest. In this review, we discuss some of the molecular SIgnals involved in cortical interneuron fate determination, and describe how this has informed the use of mouse and human embryonic stem cell biology in generating cortical interneurons in vitro. We highlight the tremendous progress that has been made recently uSIng stem cells to derive cortical interneurons, as well as challenges that have arisen. This article is part of a Special Issue entitled SI:Stems Cells in Psychiatry.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
57Brain Res. 2015 Dec -1: -1
PMID26723567
TitleSynaptic activity: An emerging player in schizophrenia.
Abstractschizophrenia is a polygenic disorder with a complex etiology. While the genetic and molecular underpinnings of the disease are poorly understood, variations in genes encoding synaptic pathways are conSIstently implicated. Although its impact is still an open question, a deficit in synaptic activity provides an attractive model to explain the cognitive etiology of schizophrenia. Recent advances in high-throughput imaging and functional studies bring new hope for the application of in vitro disease modeling with patient-derived neurons to empirically ascertain the extent to which these synaptic pathways are involved in the disease. In addition, the emergent avenue of research targeted to probe neuronal connections is revealing critical inSIght into circuitry and may influence how we think about psychiatric disorders in the near future. This article is part of a Special Issue entitled SI: Exploiting human neurons.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
58Early Interv Psychiatry 2015 Nov -1: -1
PMID26593744
TitleNewspaper coverage of mental illness in Hong Kong between 2002 and 2012: impact of introduction of a new Chinese name of psychosis.
AbstractIn Hong Kong, 'SI-jue-shi-tiao' () was officially adopted as the Chinese translation of psychoSIs in 2001. The new term covered a broader aspect of psychoSIs, compared with the original term, 'jing-shen-fen-lie' (), which gave a negative stereotype as a 'mental split-mind disorder'. The current study compared the usage of the two terms, and added evidence to the name changing as anti-stigma strategy.
The usage and themes of the new Chinese name of psychoSIs 'SI-jue-shi-tiao' was examined in 1217 local newspaper articles in comparison with the traditional Chinese name of schizophrenia 'jing-shen-fen-lie'.
Results show that an increase use of 'SI-jue-shi-tiao' was found equally across themes, whereas 'jing-shen-fen-lie' was decreaSIngly used in poSItive/neutral themes over time. The association of 'jing-shen-fen-lie' with dangerous wordings increased over time, but no change was found with the new name.
Our finding adds to literature on effects of changing new name on public stigma.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
59Brain Res. 2015 Nov -1: -1
PMID26581337
TitleUsing hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms.
Abstractschizophrenia is a neuropsychological disorder with a strong heritable component; genetic risk for schizophrenia is conferred by both common variants of relatively small effect and rare variants with high penetrance. Genetically engineered mouse models can recapitulate rare variants, displaying some behavioral defects associated with schizophrenia; however, these mouse models cannot recapitulate the full genetic architecture underlying the disorder. Patient-derived human induced pluripotent stem cells (hiPSCs) present an alternative approach for studying rare variants, in the context of all other risk alleles. Genome editing technologies, such as CRISPR-Cas9, enable the generation of isogenic hiPSC lines with which to examine the functional contribution of SIngle variants within any genetic background. Studies of these rare variants uSIng hiPSCs have the potential to identify commonly disrupted pathways in schizophrenia and allow for the identification of new therapeutic targets. This article is part of a Special Issue entitled SI:StemsCellSInPsychiatry.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
60Brain Res. 2015 Nov 1626: 267-79
PMID26163366
TitlePaying attention to MMN in schizophrenia.
AbstractThe aim of this review is to explore the phenomenon of reduced mismatch negativity (MMN) in persons with schizophrenia and the posSIble relationship it has with attention impairments. In doing so we discuss (i) the prediction error account of MMN, (ii) reduced MMN as a faulty predictive procesSIng system in persons with schizophrenia, (iii) the role of these systems in relevance filtering and attentional resource protection, (iv) attentional impairments in persons with schizophrenia, and (v) research that has explored MMN and attention in schizophrenia groups. Our review of the literature suggests that no study has appropriately examined the functional impact of smaller MMN in schizophrenia on the performance of a concurrent attention task. We conclude that future research should explore this notion further in the hope that it might embed MMN findings within outcomes of functional SIgnificance to individuals with the illness and those providing treatment. This article is part of a Special Issue entitled SI: Prediction and Attention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
61Brain Res. 2015 Aug 1617: 7-17
PMID25463024
TitleMicroglia function during brain development: New insights from animal models.
AbstractThe role of microglia in healthy brains is just beginning to receive notice. Recent studies have revealed that these phagocytic cells control the patterning and wiring of the developing central nervous system (CNS) by regulating, amongst many other processes, programmed cell death, activity-dependent synaptic pruning and synapse maturation. Microglia also play important roles in the mature brain and have demonstrated effects on behavior. Converging evidence from human and mouse studies together raise questions as to the role of microglia in disorders of brain development such as autism and, schizophrenia. In this review, we summarize a number of major findings regarding the role of microglia in brain development and highlight some key questions and avenues for future study. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
62Brain Behav. Immun. 2015 Jan 43: 149-58
PMID25128387
TitleVagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex.
AbstractThe ratio between synaptic inhibition and excitation (SI/E) is a critical factor in the pathophySIology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in SI/E in the rodent temporal cortex. The aim of the present study was to determine whether a SImilar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (SIngle acute injections of lipopolysaccharide, LPS, 10mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-SIgnaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic ?7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or - in wild-type animals - upon application sgp130Fc. SImilar results were obtained by activating the "anti-inflammatory reflex" - a neural circuit regulating peripheral immune response - by stimulation of the vagal nerve or through peripheral administration of the ?7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-SIgnaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depresSIon.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
63Behav Pharmacol 2015 Dec 26: 766-75
PMID25769091
TitleImprovement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors.
AbstractSocial withdrawal, one of the core negative symptoms of schizophrenia, can be modelled in the social interaction (SI) test in rats uSIng N-methyl-D-aspartate receptor glutamate receptor antagonists. We have recently shown that amisulpride, an antipsychotic with a high affinity for serotonin 5-HT7 receptors, reversed ketamine-induced SI deficits in rats. The aim of the present study was to further elucidate the potential involvement of 5-HT7 receptors in the prosocial action of amisulpride. Acute administration of amisulpride (3 mg/kg) and SB-269970 (1 mg/kg), a 5-HT7 receptor antagonist, reversed ketamine-induced social withdrawal, whereas sulpiride (20 or 30 mg/kg) and haloperidol (0.2 mg/kg) were ineffective. The 5-HT7 receptor agonist AS19 (10 mg/kg) abolished the prosocial efficacy of amisulpride (3 mg/kg). The coadministration of an inactive dose of SB-269970 (0.2 mg/kg) showed the prosocial effects of inactive doses of amisulpride (1 mg/kg) and sulpiride (20 mg/kg). The anxiolytic chlordiazepoxide (2.5 mg/kg) and the antidepressant fluoxetine (2.5 mg/kg) were ineffective in reverSIng ketamine-induced SI deficits. The present study suggests that the antagonism of 5-HT7 receptors may contribute towards the mechanisms underlying the prosocial action of amisulpride. These results may have therapeutic implications for the treatment of negative symptoms in schizophrenia and other disorders characterized by social withdrawal.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
64Brain Res. 2015 Aug 1617: 93-112
PMID25736181
TitleAbnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.
AbstractExtenSIve research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adverSIty, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypotheSIs that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypotheSIs integrates findings on many contributing factors to schizophrenia, including prenatal adverSIty, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adverSIty, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypotheSIs explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
65Brain Res. 2015 Sep 1621: 294-308
PMID25619550
TitleTelencephalic neurocircuitry and synaptic plasticity in rodent spatial learning and memory.
AbstractSpatial learning and memory in rodents represent close equivalents of human episodic declarative memory, which is especially senSItive to cerebral aging, neurodegeneration, and various neuropsychiatric disorders. Many tests and protocols are available for use in laboratory rodents, but Morris water maze and radial-arm maze remain the most widely used as well as the most valid and reliable spatial tests. Telencephalic neurocircuitry that plays functional roles in spatial learning and memory includes hippocampus, dorsal striatum and medial prefrontal cortex. Prefrontal-hippocampal circuitry comprises the major associative system in the rodent brain, and is critical for navigation in phySIcal space, whereas interconnections between prefrontal cortex and dorsal striatum are probably more important for motivational or goal-directed aspects of spatial learning. Two major forms of synaptic plasticity, namely long-term potentiation, a lasting increase in synaptic strength between SImultaneously activated neurons, and long-term depresSIon, a decrease in synaptic strength, have been found to occur in hippocampus, dorsal striatum and medial prefrontal cortex. These and other phenomena of synaptic plasticity are probably crucial for the involvement of telencephalic neurocircuitry in spatial learning and memory. They also seem to play a role in the pathophySIology of two brain pathologies with episodic declarative memory impairments as core symptoms, namely Alzheimer's disease and schizophrenia. Further research emphaSIs on rodent telencephalic neurocircuitry could be relevant to more valid and reliable preclinical research on these most devastating brain disorders. This article is part of a Special Issue entitled SI: Brain and Memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
66Arch Phys Med Rehabil 2015 May 96: 799-808
PMID25613597
TitleNovel risk factors associated with current suicidal ideation and lifetime suicide attempts in individuals with spinal cord injury.
AbstractTo determine unique associations of suicidal ideation (SI) and lifetime suicide attempts (SAs) in individuals with spinal cord injury(SCI).
Cross-sectional analySIs.
Outpatient.
Individuals with SCI (N=2533) who were 18 years or older with a history of traumatic SCI.
None.
Any SI in the past 2 weeks (9-item Patient Health Questionnaire) and any lifetime SA.
Three hundred twenty-three individuals (13.3%) reported SI in the past 2 weeks and 179 (7.4%) reported lifetime SA. After controlling for other factors, both lifetime SA and current SI were associated with study SIte and current level of depresSIon. In addition, SA was associated with less education, younger age at injury, having current or past treatment of depresSIon, and having bipolar disorder or schizophrenia. SI was associated with more years SInce injury and lifetime SA. Several psychological factors were associated with current SI and lifetime SAs, including lower environmental reward and less poSItive affect. In addition, control of one's community activities and spiritual well-being were associated with current SI. In bivariate comparisons, severity of SCI was also associated with the 47% of the SAs that occurred after injury.
Several unique associations of SI and lifetime SA in individuals with SCI were identified, including level of environmental reward and control, spiritual well-being, and severity of SCI. These factors bear further investigation as prospective risk factors for suicidal behavior after SCI.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
67Mol. Psychiatry 2016 Jun 21: 768-85
PMID27046645
TitleTowards understanding and predicting suicidality in women: biomarkers and clinical risk assessment.
AbstractWomen are under-represented in research on suicidality to date. Although women have a lower rate of suicide completion than men, due in part to the less-violent methods used, they have a higher rate of suicide attempts. Our group has previously identified genomic (blood gene expresSIon biomarkers) and clinical information (apps) predictors for suicidality in men. We now describe pilot studies in women. We used a powerful within-participant discovery approach to identify genes that change in expresSIon between no suicidal ideation (no SI) and high suicidal ideation (high SI) states (n=12 participants out of a cohort of 51 women psychiatric participants followed longitudinally, with diagnoses of bipolar disorder, depresSIon, schizoaffective disorder and schizophrenia). We then used a Convergent Functional Genomics (CFG) approach to prioritize the candidate biomarkers identified in the discovery step by uSIng all the prior evidence in the field. Next, we validated for suicidal behavior the top-ranked biomarkers for SI, in a demographically matched cohort of women suicide completers from the coroner's office (n=6), by assesSIng which markers were stepwise changed from no SI to high SI to suicide completers. We then tested the 50 biomarkers that survived Bonferroni correction in the validation step, as well as top increased and decreased biomarkers from the discovery and prioritization steps, in a completely independent test cohort of women psychiatric disorder participants for prediction of SI (n=33) and in a future follow-up cohort of psychiatric disorder participants for prediction of psychiatric hospitalizations due to suicidality (n=24). Additionally, we examined how two clinical instruments in the form of apps, Convergent Functional Information for Suicidality (CFI-S) and SImplified Affective State Scale (SASS), previously tested in men, perform in women. The top CFI-S item distinguishing high SI from no SI states was the chronic stress of social isolation. We then showed how the clinical information apps combined with the 50 validated biomarkers into a broad predictor (UP-Suicide), our apriori primary end point, predicts suicidality in women. UP-Suicide had a receiver-operating characteristic (ROC) area under the curve (AUC) of 82% for predicting SI and an AUC of 78% for predicting future hospitalizations for suicidality. Some of the individual components of the UP-Suicide showed even better results. SASS had an AUC of 81% for predicting SI, CFI-S had an AUC of 84% and the combination of the two apps had an AUC of 87%. The top biomarker from our sequential discovery, prioritization and validation steps, BCL2, predicted future hospitalizations due to suicidality with an AUC of 89%, and the panel of 50 validated biomarkers (BioM-50) predicted future hospitalizations due to suicidality with an AUC of 94%. The best overall SIngle blood biomarker for predictions was PIK3C3 with an AUC of 65% for SI and an AUC of 90% for future hospitalizations. Finally, we sought to understand the biology of the biomarkers. BCL2 and GSK3B, the top CFG scoring validated biomarkers, as well as PIK3C3, have anti-apoptotic and neurotrophic effects, are decreased in expresSIon in suicidality and are known targets of the anti-suicidal mood stabilizer drug lithium, which increases their expresSIon and/or activity. Circadian clock genes were overrepresented among the top markers. Notably, PER1, increased in expresSIon in suicidality, had an AUC of 84% for predicting future hospitalizations, and CSNK1A1, decreased in expresSIon, had an AUC of 96% for predicting future hospitalizations. Circadian clock abnormalities are related to mood disorder, and sleep abnormalities have been implicated in suicide. Docosahexaenoic acid SIgnaling was one of the top biological pathways overrepresented in validated biomarkers, which is of interest given the potential therapeutic and prophylactic benefits of omega-3 fatty acids. Some of the top biomarkers from the current work in women showed co-directionality of change in expresSIon with our previous work in men, whereas others had changes in oppoSIte directions, underlying the issue of biological context and differences in suicidality between the two genders. With this study, we begin to shed much needed light in the area of female suicidality, identify useful objective predictors and help understand gender commonalities and differences. During the conduct of the study, one participant committed suicide. In retrospect, when the analyses were completed, her UP-Suicide risk prediction score was at the 100 percentile of all participants tested.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
68Horm Mol Biol Clin Investig 2016 Mar 25: 157-70
PMID26812880
TitleModel approach for stress induced steroidal hormone cascade changes in severe mental diseases.
AbstractStress was described by Cushing and Selye as an adaptation to a foreign stressor by the anterior pituitary increaSIng ACTH, which stimulates the release of glucocorticoid and mineralocorticoid hormones. The question is raised whether stress can induce additional steroidal hormone cascade changes in severe mental diseases (SMD), SInce stress is the common denominator.
A systematic literature review was conducted in PubMed, where the steroidal hormone cascade of patients with SMD was compared to the impact of increaSIng stress on the steroidal hormone cascade (a) in healthy amateur marathon runners with no overtraining; (b) in healthy well-trained elite soldiers of a ranger training unit in North Norway, who were under extreme phySIcal and mental stress, sleep deprivation, and insufficient calories for 1 week; and, (c) in soldiers suffering from post traumatic stress disorder (PTSD), schizophrenia (SI), and bipolar disorders (BD).
(a) When phySIcal stress is exposed moderately to healthy men and women for 3-5 days, as in the case of amateur marathon runners, only few steroidal hormones are altered. A mild reduction in testosterone, cholesterol and triglycerides is detected in blood and in saliva, but there was no decrease in estradiol. Conversely, there is an increase of the glucocorticoids, aldosterone and cortisol. Cellular immunity, but not specific immunity, is reduced for a short time in these subjects. (b) These changes are also seen in healthy elite soldiers exposed to extreme phySIcal and mental stress but to a somewhat greater extent. For instance, the aldosterone is increased by a factor of three. (c) In SMD, an irreverSIble effect on the entire steroidal hormone cascade is detected. Hormones at the top of the cascade, such as cholesterol, dehydroepiandrosterone (DHEA), aldosterone and other glucocorticoids, are increased. However, testosterone and estradiol and their metabolites, and other hormones at the lower end of the cascade, seem to be reduced. 1) The rate and extent of reduction of the androgen metabolites may cause a decrease of cellular and specific immunity which can lead to viral and bacterial infections; joint and stomach inflammation; general pain; and allergic reactions. 2) The decrease in testosterone, and estradiol in SMD may have detrimental effects in cell repair as the estradiol metabolite, 2-methoxy-estradiol (2ME2), helps to transforms stem cells into functional cells. As dopamine and 2ME2 are inversely metabolized via various forms of catechol-O-methyl transferase (COMT), well-being and hypertenSIon may be related. 2ME2 is related to vascular endothelial growth factor (VEGF), which regulates blood capillary growth and O2 supply. As reduced O2 is a key marker of stress, the increase of glucocorticoids in all forms of mental and phySIcal stress cannot counterbalance the reduced 2ME2 in cellular and mental stress. The increased cholesterol and triglycerides are related to stroke and infarction, contributing to a reduced life expectancy in SMD between 14 and 20 years. The increase of aldosterone leads to increases in anxiety, edema, and lung infections.
IncreaSIng mental and phySIcal stress is related to systematic deviations in the steroidal hormone cascade in the non-psychotic state, which then may cause life threatening co-morbidities in PTSD, SI, and BD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
69Neurosci. Res. 2016 Apr -1: -1
PMID27091613
TitleDistinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597.
AbstractThe fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expresSIon in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expresSIon in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expresSIon was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a SImilar c-Fos expresSIon pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppresSIon of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
70Brain Res. 2016 May 1638: 161-6
PMID26100334
TitleThe role of the NG2 proteoglycan in OPC and CNS network function.
AbstractIn the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular SIgnaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adheSIve function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by ?- and ?-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This procesSIng leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focuSIng on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
71Transplant. Proc. 2016 Mar 48: 386-90
PMID27109962
TitleLiver Transplantation and Abuse of Drugs and Alcohol: A Correlation Between Scales of the MMPI-2.
AbstractClinical practice requires an accurate psychological assessment of subjects with clinical history of alcohol abuse and/or substance abuse (abuse history [AH]) for therapeutic choice. This study aims to identify SIgnificant correlations between the Minnesota MultiphaSIc Personality Inventory (MMPI)-2 scales in patients awaiting liver transplantation.
We evaluated a personality questionnaire containing MMPI-2 scales in the sample of 308 patients (81.8% males and 18.2% females) awaiting liver transplantation. The AH group composed 44.49% of patients and in the abuse free (AF) group, 55.51%. Scales were compared uSIng Shapiro-Wilk test and Mann-Whitney U test. Interrelationships were examined uSIng Spearman's correlation.
This analySIs found 27 scales of the MMPI-2 that were statistically different between 2 groups (AF and AH). In the AH group, we found a SIgnificant correlation between the following pairs of scales: schizophrenia Scale (Sc) with the Addictions Potential Scale, Social IntroverSIon scale (SI) with the Psychopathic Deviate scale (Pd), and Social Discomfort scale with Pd; the ES scale was negatively correlated with the Sc and SI scales. This interim study showed that the understanding of these indicators is crucial both for the assessment accuracy and for a prediction of the degree of therapy compliance after the transplantation.
The scales of the MMPI-2 indicated a marked tendency to emotional rigidity, a lack of self-esteem and susceptibility judgment. Social introverSIon and social discomfort trends lead to impulSIve behavior and deviant actions that combine poorly with good compliance with treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
72Cogn Neuropsychiatry 2016 Mar 21: 168-81
PMID27022005
TitleSelf-imagination can enhance memory in individuals with schizophrenia.
AbstractPrevious research has demonstrated that self-referential strategies can be applied to improve memory in various memory- impaired populations. However, little is known regarding the relative effectiveness of self-referential strategies in schizophrenia patients. The main aim of this study was to assess the effectiveness of a new self-referential strategy known as self- imagination (SI) on a free recall task.
Twenty schizophrenia patients and 20 healthy controls intentionally encoded words under five instructions: superficial procesSIng, semantic procesSIng, semantic self-referential procesSIng, episodic self-referential procesSIng and semantic self- imagining. Other measures included depresSIon, psychotic symptoms and cognitive measures.
We found a SI effect in memory as self- imagining resulted in better performance in memory retrieval than semantic and superficial encoding in schizophrenia patients. The memory boost for self-referenced information in comparison to semantic procesSIng was not found for other self-referential strategies. In addition no relationship between clinical variables and free recall performances was found. In controls, the SI condition did not result in better performance. The three self-referential strategies yielded better free recall than both superficial and semantic encoding.
This study provides evidence of the clinical utility of self-imagining as a mnemonic strategy in schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
73Brain Res. 2016 Jun 1641: 217-33
PMID26790349
TitleNorepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.
AbstractAmong the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA SIgnaling is implicated in the pathogeneSIs of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic SIgnaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmisSIons in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, SIgnaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extenSIvely and modulate synaptic function by activating distinctly different receptor subtypes and SIgnaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
74Eur Neuropsychopharmacol 2016 Jan 26: 3-14
PMID26655189
TitleEffects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.
AbstractNegative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have conSIstently demonstrated, sub-chronic PCP SIgnificantly impaired behavior in these tests. Deficits were SIgnificantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In concluSIon, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
75Brain Res. 2016 May 1638: 105-13
PMID26459991
TitleAbnormalities of cingulate cortex in antipsychotic-nave chronic schizophrenia.
AbstractWhile several morphometric studies have postulated a critical contribution of the cingulate cortex (CC) to the pathophySIology of schizophrenia based on abnormalities in CC volume, other studies have been inconcluSIve. Most such studies have focused only on changes in cortical volume, whereas other morphometric parameters such as surface area and cortical thickness could be more relevant and posSIbly account for these discrepancies. Furthermore, factors such as antipsychotic drug use and treatment duration may also influence cortical morphology. To clarify the association between schizophrenia and CC deficits, we investigated morphometric abnormalities of the CC in antipsychotic drug (AD)-nave chronic schizophrenia patients by comparing T1-weighted magnetic resonance images (T1WI-MRI) from patients (n=17) to healthy controls (n=17) uSIng the surface-based morphometry program FreeSurfer. Partial correlations were examined between abnormal morphometric measures and both clinical variables and cognitive performance scores. Compared to healthy controls, drug-nave schizophrenia patients exhibited SIgnificantly lower volumes in both left rostral anterior CC (rACC) and left posterior CC (PCC). These reductions in CC volume resulted from reduced surface area rather than reduced cortical thickness. There was also a SIgnificant relationship between left PCC volume and working memory in patients. No SIgnificant correlations were observed between CC volume and clinical variables. The results suggest that abnormalities in the CC as manifested by reduced surface area may contribute to cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled SI: PSC and the brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
76Brain Res. 2016 May 1638: 74-87
PMID26423935
TitlePotential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer?s and Parkinson?s diseases.
AbstractSeveral neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid poSItive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmisSIon in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmisSIon, uSIng preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much conSIderation because of their ability for disperSIon, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for eaSIng neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer?s disease and Parkinson?s disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to conSIdering the posSIble clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphaSIzed. This article is part of a Special Issue entitled SI: PSC and the brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal