| 1 | Schizophr. Res. 2000 May 43: 57-64 |
|---|---|
| PMID | 10828415 |
| Title | Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics. |
| Abstract | In the 1940s and 1950s, prefrontal lobotomy was widely used to treat aggressive, disruptive and psychotic behavior in schizophrenics. Subsequent observations have confirmed its ineffectiveness in schizophrenia. Few studies have addressed its long-term consequences. We conducted tests of frontal function, behavior (Frontal Behavioral Inventory), psychopathology (PANSS), neurological examinations and CT scans in 19 chronically institutionalized schizophrenic patients (mean age 74) who had undergone orbitofrontal leukotomy between 1948 and 1972 and 11 controls (mean age 74) matched for age, length of hospitalization, education, and diagnosis. There were no significant differences between leukotomized patients and controls on: Folstein Mini-Mental score (leuko 22.13+/-5.66; controls 23.55+/-5.93), utilization behavior, Luria alternating written and motor sequences, verbal fluency, imitation behavior, motor impersistence, primitive reflexes, or psychopathology. Significant differences were found on CLOCK drawing and on the go/no-go test, which may reflect the presence of an orbitofrontal lesion in the leukotomized group. There was a tendency for the leukotomized group to have fewer indices of frontal behavioral dysfunction. Both groups showed comparable impairment on the Stroop test and cognitive rigidity on the Odd Man Out test of category shifting. With few exceptions, elderly leukotomized and nonleukotomized schizophrenic patients show varying degrees of distractibility, difficulty in set shifting, poor planning and organization, susceptibility to interference, primitive reflexes and signs of global cognitive impairment. Allowing for the small sample size, variability in the surgical frontal lesion, and the long interval from surgery to testing, these observations likely reflect the long-term consequences of severe schizophrenia in both groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Int J Geriatr Psychiatry 2000 Jul 15: 638-43 |
| PMID | 10918345 |
| Title | Comparison of a clock drawing test in elderly schizophrenia and Alzheimer's disease patients: a preliminary study. |
| Abstract | The objective of this study was to compare between the quantitative and qualitative aspects of a CLOCK drawing test in elderly schizophrenic and Alzheimer's disease (AD) patients. Three independent raters performed a retrospective analysis of the CLOCK drawing item from the Cambridge Cognitive Examination (CAMCOG), in long-term open wards of a public psychiatric hospital and an outpatient psychogeriatric clinic. The study group comprised 21 elderly schizophrenic patients ('graduates') and 21 AD patients matched for gender and education, and cognitive impairment confirmed by a Folstein mini-mental state examination (MMSE) score of 18-23. The CLOCK Drawing Interpretation Scale (CDIS) was the measure used. schizophrenic patients were significantly younger than AD patients (63.5 versus 81.3 years, p<0.0001), however, similar concerning gender, education, MMSE and CAMCOG scores. CDIS scores were not correlated with age in eight group. Inter-rater reliability was high (range 0.84-0.97). No significant differences between patient groups were found in mean CDIS total scores. A CDIS specific item analysis revealed that schizophrenic patients were significantly less impaired than AD patients on three out of 20 items: Number 7 (most symbols are aligned in a CLOCKwise or a rightward direction). Number 8 (all symbols are totally within a closure figure), and Number 13 (numbers do not go beyond 12). Although schizophrenic patients and AD patients had similar total scores on the CLOCK drawing test, they differed on specific test items related to spatial/planning deficit and preservation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Schizophr. Res. 2000 May 43: 57-64 |
| PMID | 10828415 |
| Title | Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics. |
| Abstract | In the 1940s and 1950s, prefrontal lobotomy was widely used to treat aggressive, disruptive and psychotic behavior in schizophrenics. Subsequent observations have confirmed its ineffectiveness in schizophrenia. Few studies have addressed its long-term consequences. We conducted tests of frontal function, behavior (Frontal Behavioral Inventory), psychopathology (PANSS), neurological examinations and CT scans in 19 chronically institutionalized schizophrenic patients (mean age 74) who had undergone orbitofrontal leukotomy between 1948 and 1972 and 11 controls (mean age 74) matched for age, length of hospitalization, education, and diagnosis. There were no significant differences between leukotomized patients and controls on: Folstein Mini-Mental score (leuko 22.13+/-5.66; controls 23.55+/-5.93), utilization behavior, Luria alternating written and motor sequences, verbal fluency, imitation behavior, motor impersistence, primitive reflexes, or psychopathology. Significant differences were found on CLOCK drawing and on the go/no-go test, which may reflect the presence of an orbitofrontal lesion in the leukotomized group. There was a tendency for the leukotomized group to have fewer indices of frontal behavioral dysfunction. Both groups showed comparable impairment on the Stroop test and cognitive rigidity on the Odd Man Out test of category shifting. With few exceptions, elderly leukotomized and nonleukotomized schizophrenic patients show varying degrees of distractibility, difficulty in set shifting, poor planning and organization, susceptibility to interference, primitive reflexes and signs of global cognitive impairment. Allowing for the small sample size, variability in the surgical frontal lesion, and the long interval from surgery to testing, these observations likely reflect the long-term consequences of severe schizophrenia in both groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Schizophr. Res. 2000 May 43: 57-64 |
| PMID | 10828415 |
| Title | Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics. |
| Abstract | In the 1940s and 1950s, prefrontal lobotomy was widely used to treat aggressive, disruptive and psychotic behavior in schizophrenics. Subsequent observations have confirmed its ineffectiveness in schizophrenia. Few studies have addressed its long-term consequences. We conducted tests of frontal function, behavior (Frontal Behavioral Inventory), psychopathology (PANSS), neurological examinations and CT scans in 19 chronically institutionalized schizophrenic patients (mean age 74) who had undergone orbitofrontal leukotomy between 1948 and 1972 and 11 controls (mean age 74) matched for age, length of hospitalization, education, and diagnosis. There were no significant differences between leukotomized patients and controls on: Folstein Mini-Mental score (leuko 22.13+/-5.66; controls 23.55+/-5.93), utilization behavior, Luria alternating written and motor sequences, verbal fluency, imitation behavior, motor impersistence, primitive reflexes, or psychopathology. Significant differences were found on CLOCK drawing and on the go/no-go test, which may reflect the presence of an orbitofrontal lesion in the leukotomized group. There was a tendency for the leukotomized group to have fewer indices of frontal behavioral dysfunction. Both groups showed comparable impairment on the Stroop test and cognitive rigidity on the Odd Man Out test of category shifting. With few exceptions, elderly leukotomized and nonleukotomized schizophrenic patients show varying degrees of distractibility, difficulty in set shifting, poor planning and organization, susceptibility to interference, primitive reflexes and signs of global cognitive impairment. Allowing for the small sample size, variability in the surgical frontal lesion, and the long interval from surgery to testing, these observations likely reflect the long-term consequences of severe schizophrenia in both groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Int J Geriatr Psychiatry 2000 Jul 15: 638-43 |
| PMID | 10918345 |
| Title | Comparison of a clock drawing test in elderly schizophrenia and Alzheimer's disease patients: a preliminary study. |
| Abstract | The objective of this study was to compare between the quantitative and qualitative aspects of a CLOCK drawing test in elderly schizophrenic and Alzheimer's disease (AD) patients. Three independent raters performed a retrospective analysis of the CLOCK drawing item from the Cambridge Cognitive Examination (CAMCOG), in long-term open wards of a public psychiatric hospital and an outpatient psychogeriatric clinic. The study group comprised 21 elderly schizophrenic patients ('graduates') and 21 AD patients matched for gender and education, and cognitive impairment confirmed by a Folstein mini-mental state examination (MMSE) score of 18-23. The CLOCK Drawing Interpretation Scale (CDIS) was the measure used. schizophrenic patients were significantly younger than AD patients (63.5 versus 81.3 years, p<0.0001), however, similar concerning gender, education, MMSE and CAMCOG scores. CDIS scores were not correlated with age in eight group. Inter-rater reliability was high (range 0.84-0.97). No significant differences between patient groups were found in mean CDIS total scores. A CDIS specific item analysis revealed that schizophrenic patients were significantly less impaired than AD patients on three out of 20 items: Number 7 (most symbols are aligned in a CLOCKwise or a rightward direction). Number 8 (all symbols are totally within a closure figure), and Number 13 (numbers do not go beyond 12). Although schizophrenic patients and AD patients had similar total scores on the CLOCK drawing test, they differed on specific test items related to spatial/planning deficit and preservation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Lancet 2000 Feb 355: 614-7 |
| PMID | 10696982 |
| Title | Community care and criminal offending in schizophrenia. |
| Abstract | The introduction of community care in psychiatry is widely thought to have resulted in more offending among the seriously mentally ill. This view affects public policy towards and public perceptions of such people. We investigated the association between the introduction of community care and the pattern of offending in patients with schizophrenia in Victoria, Australia. We established patterns of offending from criminal records in two groups of patients with schizophrenia over their lifetime to date and in the 10 years after their first hospital admission. One group was first admitted in 1975 before major deinstitutionalisation in Victoria, the second group in 1985 when community care was becoming the norm. Each patient was matched to a control, by age, sex, and place of residence to allow for changing patterns of offending over time in the wider community. Compared with controls, significantly more of those with schizophrenia were convicted at least once for all categories of criminal offending except sexual offences (relative risk of offending in 1975=3.5 [95% CI 2.0-5.5), p=0.001, in 1985=3.0 [1.9-4.9], p=0.001). Among men, more offences were committed in the 1985 group than the 1975 group, but this was matched by a similar increase in convictions among the community controls. Those with schizophrenia who had also received treatment for substance abuse accounted for a disproportionate amount of offending. Analysis of admission data for the patients and the total population of admissions with schizophrenia showed that although there had been an increase of 74 days per annum spent in the community for each of the study population as a whole, first admissions spent only 1 more day in the community in 1985 compared with 1975. Increased rates in criminal conviction for those with schizophrenia over the last 20 years are consistent with change in the pattern of offending in the general community. Deinstitutionalisation does not adequately explain such change. Mental-health services should aim to reduce the raised rates of criminal offending associated with schizophrenia, but turning the CLOCK back on community care is unlikely to contribute towards any positive outcome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Hum. Genet. 2001 Aug 109: 136-42 |
| PMID | 11511917 |
| Title | The polyglutamine motif is highly conserved at the Clock locus in various organisms and is not polymorphic in humans. |
| Abstract | Circadian rhythms play a central role in diverse physiological phenomena and the recent years have witnessed the identification of a number of genes responsible for the maintenance of these rhythms. One of these is the CLOCK gene, which was first identified in mouse and subsequently in a large number of organisms, including humans. The human CLOCK gene has been proposed as a possible candidate for disorders affected by alterations of circadian rhythm, including bipolar disorder and schizophrenia. This gene contains a highly conserved polyglutamine motif, that in humans is coded for by CAG repeats. In view of the involvement of CAG repeat expansion in a number of neuro-psychiatric disorders, we have sought to determine the polymorphism status of CAG repeats at the CLOCK locus in humans. Our analysis of 190 unrelated individuals, who included patients suffering from bipolar disorder and schizophrenia, indicated that the repeat, which consisted of 6 CAG triplets, was not polymorphic in humans. An analysis of the repeat in non-human primates and other organisms revealed that the glutamine stretch is shortest in humans and baboons, and longest in Drosophila and zebrafish. A study of various Drosophila species revealed that the repeat number is highly polymorphic, ranging from 25 to 33 pure glutamine repeats. Unlike most other microsatellites, the CAG repeat stretch at the CLOCK locus in humans is smaller than its homologues in non-human primates. We propose that glutamine repeat size is functionally important in this gene and thus tightly regulated. The variation in repeat number is probably deleterious to the individual, resulting in the maintenance of a short and invariable repeat structure in the human population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Med. Hypotheses 2001 Jan 56: 20-3 |
| PMID | 11133250 |
| Title | Psychiatric aspects of jet lag: review and hypothesis. |
| Abstract | Jet lag is a travel-induced circadian rhythm phenomenon that afflicts healthy individuals following long- distance flights through several time zones. The typical jet-lag manifestations - insomnia during local sleep time, day fatigue, reduced concentration, irritability, and exhaustion with mild depression - are attributed to transient desynchronization in the circadian rhythm until the internal biological CLOCK is rephased to the new environmental conditions. There is strong evidence relating affective disorders with circadian rhythm abnormalities. Less convincing suggestions relate jet lag to psychosis. It can be hypothesized that in predisposed individuals jet lag may play a role in triggering exacerbation or even de novo affective disorders. Furthermore, we propose the possibility that psychosis and even schizophrenia can be elicited by jet lag. This outlook gains its support from case studies and some common underlying phase-advanced biological denominators involved in both jet lag sufferers and psychotic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Cell. Mol. Neurobiol. 2001 Dec 21: 605-16 |
| PMID | 12043836 |
| Title | Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. |
| Abstract | To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological CLOCK as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Community Genet 2002 -1 5: 171-7 |
| PMID | 14960887 |
| Title | Common psychiatric diseases and human genetic variation. |
| Abstract | A better understanding of human genetic variation is important in assessing disease epidemiology and phenotypic variation, and may be critical in evaluating genetic aspects of common genetic diseases, such as schizophrenia, bipolar disease and Parkinson's. These diseases are particularly difficult to investigate as there are few peripheral markers, and although a genetic aetiology has long been suspected, robust findings have been hard to establish. Variations in alleles at 13 tri-nucleotide gene loci expressed in the brain and implicated in several neurodegenerative diseases, as well as certain other loci, were examined in the Indian population for comparison with other major ethnic groups. In the Indian population, the distribution of alleles at the Machado-Joseph disease locus was similar to the Western European pattern of distribution. Analysis of haplotypes at the locus for Huntington's disease suggested multiple origins, and possible effects of population admixture because of the recent history of the country. At other alleles of neuropsychiatric interest (dopamine receptor, serotonin receptor, serotonin transporter, alcohol dehydrogenase), allele frequencies in the Indian population differed from other populations. Interspecies comparison suggests a gradual expansion in repeat size, with the exception of the CLOCK gene, which displays a contraction of CAG repeat numbers. World-wide differences in disease phenotypes need to be explored, and an appreciation of their genetic basis may provide a window of opportunity for improving our knowledge of the underlying genetic mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Schizophr. Res. 2003 Feb 59: 173-9 |
| PMID | 12414073 |
| Title | Clock drawing test in institutionalized patients with schizophrenia compared with Alzheimer's disease patients. |
| Abstract | The impaired performance of Alzheimer's disease (AD) patients on the CLOCK drawing test (CDT) relative to age-matched normal controls is a well-documented finding in the literature. On the other hand, there is sparse information regarding the use of this test in schizophrenia. We examined three groups of subjects matched for gender and education: institutionalized patients with schizophrenia (n = 32), patients with AD (n = 32), and normal controls (n = 36). The CDT ("free-drawn", "pre-drawn", and three "examiner" conditions) and Mini-Mental State Examination (MMSE) were administered to all participants. In patients with schizophrenia, symptom severity was assessed with the Brief Psychiatric Rating Scale (BPRS). Patients with schizophrenia were significantly younger than AD patients and normal controls (56.78 versus 71.41 and 66.25, respectively), and normal controls had significantly higher MMSE scores than patients with schizophrenia and AD (27.58 versus 20.75 and 18.44, respectively). In all of the CLOCK conditions, the two patient groups performed significantly poorer than the normal controls, with the exception of the "pre-drawn" CLOCK in which AD patients also performed worse than patients with schizophrenia. Age and duration of illness did not correlate significantly with CDT scores. When MMSE scores were used as a covariate, all significant differences on the CDT among the three groups disappeared, with the exception of the "pre-drawn" CLOCK (AD patients had lower scores than both control and schizophrenia groups). In patients with schizophrenia, scores on the BPRS were not related with any CDT variable. Institutionalized patients with schizophrenia and AD patients showed similar deficits on a neuropsychological test sensitive to changes in visual-analytic function, attention, receptive language, and executive functions such as planning, organization, and simultaneous processing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | J Med Assoc Thai 2004 Dec 87: 1526-9 |
| PMID | 15822553 |
| Title | Environmental reduplication in a patient with right middle cerebral artery occlusion. |
| Abstract | Environmental reduplication or reduplicative paramnesia is one of the content-specific delusions (CSD) which is characterized by reduplication of places. CSD has been reported in focal and diffuse cerebral disorders. A focal lesion such as frontal lobes and the right hemispheric lesion have been documented The authors describe a 66 year-old woman who had a delusion of misidentification for place one month after right middle cerebral artery occlusion. The patient did not have any history of schizophrenia or other psychiatric diseases. The patient believed that her car, furniture and house were duplicated. She also mentioned that her son and friends tried to takeover all of her properties and told everyone that she was insane. The prominent cortical signs were tactile and visual neglect. Neuropsychological assessments revealed poor attention but she had neither confusion nor dementia. CLOCK drawing and construction tests revealed visuospatial impairment which was compatible with non-dominant hemispheric abnormality. MRI showed evidence of cerebral infarction in the right middle cerebral artery territory. Only one similar patient who had an intracerbral hematoma of the right frontal lobe has been reported in the literature. The role of occipito-parietal and fronto-temporal lobes or their connections in environmental reduplication is proposed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Bull. Acad. Natl. Med. 2004 -1 188: 285-96; discussion 296 |
| PMID | 15506719 |
| Title | [From circular insanity (in double form) to the bipolar spectrum: the chronic tendency for depressive recurrence]. |
| Abstract | From a cycling standpoint, "circular insanity" (Falret) and "dual-form insanity" (Baillarger), both described in hospital patients in 1854, are at the severe end of the spectrum of what we now call "bipolar disorders". Falret was prescient in suggesting that circular insanity was rare in the community, where depressive cycles are prevalent. These disorders are now respectively referred to as the "hard" (manic-depressive) and "soft" (bipolar spectrum) phenotypes of the disorder. This paper focuses on the latter, more prevalent depressive expressions of the spectrum, which share with the manic and circular forms a lifelong tendency to recur. Their cyclicity may involve putative "CLOCK genes". The genetics of psychotic mania overlaps somewhat with the genetics of schizophrenia. As regards depressive recurrence, putative genetic factors have been identified, including a polymorphism of the serotonin transporter, which significantly increases the subject's vulnerability to stress; a mediating pathogenetic variable appears to be temperamental dysregulation (e.g. neuroticism and cyclothymic lability), which produces hyperemotional reactivity to such stressors. The growing recognition that many depressive recurrences belong to a broad spectrum, affecting 5-10% of the population, represents a new public health challenge. Although the new class of serotoninergic antidepressants offer a practical approach to the management of depressive episodes, further research is needed to determine the point of the spectrum at which mood-stabilizing therapy should be started--and in what combinations--in order to prevent recurrence and suicide. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Psychiatry Res 2004 Jan 121: 229-38 |
| PMID | 14675742 |
| Title | Clock Drawing Test in patients with schizophrenia. |
| Abstract | Investigations of the usefulness of the CLOCK Drawing Test (CDT) in schizophrenia have focused primarily on institutionalized or elderly patients. The purpose of the present study was to compare CDT performance of patients with schizophrenia living in the community with that of normal controls. Fifty-three patients with schizophrenia were compared with 66 age- and gender-matched normal controls. The CDT ('free-drawn', 'pre-drawn' and three 'examiner' conditions) and the Mini-Mental State Examination (MMSE) were administered to all participants. In patients with schizophrenia, symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS). Patients with schizophrenia had significantly lower scores on the MMSE and the five CDT conditions than the control group. When MMSE scores and level of education were included in the comparisons as covariates, the differences between the two groups remained significant. MMSE scores of the patients with schizophrenia correlated significantly with four CLOCK conditions: 'free-drawn' 'pre-drawn' and two of the 'examiner' conditions (11:10 and 8:20). Poorer performance on the CDT correlated with higher scores on the PANSS positive symptoms subscale. Qualitative analysis of the CLOCKs that were drawn revealed specific errors in the schizophrenia group relating to frontal processes: difficulty placing numbers in the correct position, failure to indicate the minute targets, displacement of the minute hand from the minute number, and failure to draw a longer minute hand. The fact that the CDT is sensitive enough to detect the cognitive impairment inherent in schizophrenia, as well as being correlated with symptom severity, makes this test useful in roughly assessing cognitive state in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Brain Cogn 2005 Jun 58: 109-18 |
| PMID | 15878731 |
| Title | Interval-timing deficits in individuals at high risk for schizophrenia. |
| Abstract | A duration-bisection procedure was used to study the effects of signal modality and divided attention on duration classification in participants at high genetic risk for schizophrenia (HrSz), major affective disorder (HrAff), and normal controls (NC). Participants learned short and long target durations during training and classified probe durations during test. All groups classified visual signals as shorter than equivalent duration auditory signals. However, the difference between auditory and visual signal classification was significantly larger for the HrSz group than for the NC group. We posit a model in which there is a CLOCK rate difference between auditory and visual signals due to an attentional effect at the level of a mode switch that gates pulses into an accumulator. This attentionally mediated CLOCK rate difference was larger for the HrSz participants than for the NC participants, resulting in a larger auditory/visual difference for the HrSz group. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Int J Clin Pharmacol Ther 2006 Nov 44: 589-92 |
| PMID | 17176626 |
| Title | Beneficial effect of long-acting injectable risperidone on the neurocognitive deficit of a schizophrenic patient: A case report. |
| Abstract | We report the case of a 37-year-old female patient suffering from schizophrenia, disorganized type. Adherence to treatment was always a major problem. During the last 2 years the patient was disorganized and was refusing treatment. Since the patient was already receiving a very high (double) dose per os, it was decided to administer two 50 ml ampoules of long-acting, injectable risperidone plus 5 mg of haloperidol per os daily. After 80 days of treatment, all positive, negative and even neurocognitive symptoms improved markedly. Extrapyramidal side effects did not appear at any stage of treatment. The most impressive neurocognitive improvement concerned the CLOCK drawing test, which was in parallel with her improvement in both the positive and negative symptoms of the PANSS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Int J Clin Pharmacol Ther 2006 Nov 44: 589-92 |
| PMID | 17176626 |
| Title | Beneficial effect of long-acting injectable risperidone on the neurocognitive deficit of a schizophrenic patient: A case report. |
| Abstract | We report the case of a 37-year-old female patient suffering from schizophrenia, disorganized type. Adherence to treatment was always a major problem. During the last 2 years the patient was disorganized and was refusing treatment. Since the patient was already receiving a very high (double) dose per os, it was decided to administer two 50 ml ampoules of long-acting, injectable risperidone plus 5 mg of haloperidol per os daily. After 80 days of treatment, all positive, negative and even neurocognitive symptoms improved markedly. Extrapyramidal side effects did not appear at any stage of treatment. The most impressive neurocognitive improvement concerned the CLOCK drawing test, which was in parallel with her improvement in both the positive and negative symptoms of the PANSS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Psychol Rep 2006 Feb 98: 39-42 |
| PMID | 16673949 |
| Title | Interrater reliability of scores derived from two methods for scoring the clock drawing test. |
| Abstract | Scores on the CLOCK Drawing Test have long been considered a useful screening tool for neuropsychological dysfunction, and a number of scoring methods have been developed to evaluate various aspects of performance. This study compared quantitative and qualitative scoring by briefly trained students on 145 CLOCK drawings produced by patients in a geriatric psychiatry outpatient clinic to estimate the interrater reliability of the methods, user's acceptance of the methods, and whether the methods provide differential diagnosis. Both systems showed acceptable interrater reliability. Using the quantitative method, raters scored drawings by patients with organic mental disease as more impaired than those patients diagnosed as depressed or schizophrenic. Results suggest that the CLOCK Drawing Test is a reliable screening tool for cognitive impairment in a geropsychiatric population, but the scoring methods examined do not yet appear psychometrically sound enough to provide a differential diagnosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Med. Hypotheses 2007 -1 69: 849-51 |
| PMID | 17376600 |
| Title | Cryptochrome1 maybe a candidate gene of schizophrenia. |
| Abstract | During the last 10 years, we have witnessed major progress in the genetic study of schizophrenia, but gene-mapping efforts have been hampered by the complex mode of inheritance and the likelihood of multiple genes of small effect. In view of the complexity, it may be instructive to understand the biological bases for pathogenesis. Extensive disruption in circadian function is known to occur among schizophrenia patients. If circadian dysfunction can be established as an 'endophenotype' for schizophrenia, it may not only enable the identification of more homogenous sub-groups, but also facilitate the genetic analyses. Therefore, circadian dysfunction maybe underlies the pathogenesis of schizophrenia and would be logical to investigate polymorphisms of genes encoding key proteins that mediate circadian rhythms. Cryptochrome1 (Cry1), located in a chromosomal region 12q23-q24.1, performs predominantly regulatory function in circadian CLOCK and which is close to a linkage hotspot (12q24) of schizophrenia. Recent studies also found that Cry1 gene interacted with antipsychotic drugs and dopamine system which played a core role in the pathophysiology of schizophrenia. Based on these findings, we speculate that Cry1 was the candidate gene of schizophrenia. The proposition may have new clues on the development of genetic study on complex diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Mar 144B: 129-58 |
| PMID | 17266109 |
| Title | Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. |
| Abstract | Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, CLOCK genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Dialogues Clin Neurosci 2007 -1 9: 333-42 |
| PMID | 17969870 |
| Title | The role of circadian clock genes in mental disorders. |
| Abstract | The study of molecular CLOCK mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian CLOCK genes in MDD. There is also relatively little information regarding the role of CLOCK genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of CLOCK genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master CLOCK, which is supported by postmortem studies of CLOCK gene expression in the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Eur Neuropsychopharmacol 2007 Mar 17: 273-6 |
| PMID | 17116390 |
| Title | CLOCK gene T3111C polymorphism is associated with Japanese schizophrenics: a preliminary study. |
| Abstract | The CLOCK gene has attracted attention due to its influence on the circadian rhythm, as well as its impacts on the dopaminergic system. We conducted a preliminary study to examine whether the T3111C single nucleotide polymorphism of the CLOCK gene is associated with the development of schizophrenia by examining samples from schizophrenics (n=145) and normal controls (n=128). Both genotype and allele frequencies were significantly different between schizophrenics and controls (p=0.022, p=0.015, respectively). schizophrenics had a significantly higher frequency of the C allele compared to controls (odds ratio 1.76, 95% CI 1.12-2.75). In particular, disorganized and residual type schizophrenics had significantly higher C allele frequencies than controls (p=0.004 and p=0.037, respectively). Our results suggest that the T3111C polymorphism of the CLOCK gene is associated with schizophrenia. It is important to explore the association between CLOCK and dopamine function, and to examine the impact of CLOCK on phenotypes such as symptoms and drug response in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Eur Neuropsychopharmacol 2007 Mar 17: 273-6 |
| PMID | 17116390 |
| Title | CLOCK gene T3111C polymorphism is associated with Japanese schizophrenics: a preliminary study. |
| Abstract | The CLOCK gene has attracted attention due to its influence on the circadian rhythm, as well as its impacts on the dopaminergic system. We conducted a preliminary study to examine whether the T3111C single nucleotide polymorphism of the CLOCK gene is associated with the development of schizophrenia by examining samples from schizophrenics (n=145) and normal controls (n=128). Both genotype and allele frequencies were significantly different between schizophrenics and controls (p=0.022, p=0.015, respectively). schizophrenics had a significantly higher frequency of the C allele compared to controls (odds ratio 1.76, 95% CI 1.12-2.75). In particular, disorganized and residual type schizophrenics had significantly higher C allele frequencies than controls (p=0.004 and p=0.037, respectively). Our results suggest that the T3111C polymorphism of the CLOCK gene is associated with schizophrenia. It is important to explore the association between CLOCK and dopamine function, and to examine the impact of CLOCK on phenotypes such as symptoms and drug response in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Schizophr Bull 2007 Sep 33: 1162-70 |
| PMID | 16956984 |
| Title | A virtual reality apartment as a measure of medication management skills in patients with schizophrenia: a pilot study. |
| Abstract | Performance on a novel, virtual reality (VR) assessment of medication management skills, the Virtual Reality Apartment Medication Management Assessment (VRAMMA), was investigated in 25 patients with schizophrenia and 18 matched healthy controls. The VRAMMA is a virtual 4-room apartment consisting of a living room with an interactive CLOCK and TV, a bedroom, a kitchen, and a bathroom with an interactive medicine cabinet. After an exploratory phase, participants were given a mock prescription regimen to be taken 15 minutes later from pill bottles located in the medicine cabinet in the bathroom of the virtual environment. The VRAMMA was administered with a validated measure of medication management skills, several neurocognitive tests, and a symptom scale. Results revealed that (1) schizophrenic patients made significantly more quantitative errors in the number of pills taken, were less accurate at taking the prescribed medications at the designated time, and checked the interactive CLOCK less frequently than healthy controls; (2) in patients with schizophrenia, there was significant agreement in classification of adherence vs nonadherence between a validated measure of medication management skills and the VRAMMA; and (3) in patients with schizophrenia, years of education and a measure of verbal learning and memory were linked to quantitative errors on the VRAMMA, while positive symptoms, specifically delusional symptoms, were inversely linked to distance traveled within the VRAMMA. This is the first study, to our knowledge, to provide evidence for the utility of VR technology in the assessment of instrumental role functioning in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Schizophr Bull 2007 Sep 33: 1162-70 |
| PMID | 16956984 |
| Title | A virtual reality apartment as a measure of medication management skills in patients with schizophrenia: a pilot study. |
| Abstract | Performance on a novel, virtual reality (VR) assessment of medication management skills, the Virtual Reality Apartment Medication Management Assessment (VRAMMA), was investigated in 25 patients with schizophrenia and 18 matched healthy controls. The VRAMMA is a virtual 4-room apartment consisting of a living room with an interactive CLOCK and TV, a bedroom, a kitchen, and a bathroom with an interactive medicine cabinet. After an exploratory phase, participants were given a mock prescription regimen to be taken 15 minutes later from pill bottles located in the medicine cabinet in the bathroom of the virtual environment. The VRAMMA was administered with a validated measure of medication management skills, several neurocognitive tests, and a symptom scale. Results revealed that (1) schizophrenic patients made significantly more quantitative errors in the number of pills taken, were less accurate at taking the prescribed medications at the designated time, and checked the interactive CLOCK less frequently than healthy controls; (2) in patients with schizophrenia, there was significant agreement in classification of adherence vs nonadherence between a validated measure of medication management skills and the VRAMMA; and (3) in patients with schizophrenia, years of education and a measure of verbal learning and memory were linked to quantitative errors on the VRAMMA, while positive symptoms, specifically delusional symptoms, were inversely linked to distance traveled within the VRAMMA. This is the first study, to our knowledge, to provide evidence for the utility of VR technology in the assessment of instrumental role functioning in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J. Neurochem. 2008 Mar 104: 1450-65 |
| PMID | 18028338 |
| Title | Cholecystokinin-2 receptor mediated gene expression in neuronal PC12 cells. |
| Abstract | Cholecystokinin (CCK) is abundantly expressed in the CNS, in which it regulates feeding behavior and long-term memory. Moreover, CCK has been implicated in mental disorders, such as anxiety and schizophrenia. Despite its manifest physiological and pathophysiological role, the molecular targets of neuronal CCK are incompletely understood. To identify genes regulated by neuronal CCK, we generated neuronal PC12 cells stably expressing the CCK-2 receptor (CCK-2R) and treated the cells with sulphated CCK-8 for 2-16 h, before the global expression profile was examined. The changes in gene expression peaked after 2 h, with 67 differentially expressed transcripts identified. A pathway analysis indicated that CCK was implicated in the regulation of the circadian CLOCK system, the plasminogen system and cholesterol metabolism. But transcripts encoding proteins involved in dopamine signaling, ornithine decarboxylase (ODC) regulation, memory and epidermal growth factor receptor (EGFR) signaling were also found. Several target genes contained cAMP response elements (CREs), serum response elements (SREs), activator protein 1 (AP1) elements and GC-rich regions, but otherwise no common regulatory promoter element could be identified. Comparison with forskolin- and nerve growth factor (NGF)-treated PC12 cells showed that CCK induced a separate set of target genes. Taken together, we propose that neuronal CCK may have a role in the regulation of the circadian rhythm, the metabolism of cerebral cholesterol and in the regulation of the plasminogen system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Eur Neuropsychopharmacol 2008 Feb 18: 117-21 |
| PMID | 17728110 |
| Title | Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: A preliminary study. |
| Abstract | schizophrenia is comprised of several debilitating symptoms. Antipsychotics offer an effective treatment for positive symptoms, while the negative signs and cognitive deficits are usually treatment-resistant. It was suggested that glutamate dysregulation may be involved in the neuropathology of schizophrenia, mainly through NMDA dysfunction. We hypothesized that addition of memantine, a weak non-selective NMDA receptor antagonist approved for dementia, to antipsychotics would improve the clinical status of un-remitted schizophrenia patients, notably the negative signs and cognitive deficits. Seven schizophrenia patients, were included in a six-week open-label study, with weekly increasing dosage (5, 10, 15, 20 mg) of memantine added to their on-going antipsychotic treatment. We found a significant improvement of the PANSS score (baseline 116.28+/-21.9 vs. 97.86+/-24.48 after six weeks, t=5.98, p<0.001) with the most prominent improvement (21%) in negative signs sub-scale (baseline 40+/-6.38 vs. 31.71+/-7.76 after six weeks, t=5.87, p<0.001). Cognitive status, measured with the Neurobehavioral Cognitive Examination (NCSE) and CLOCK Drawing Test (CDT) showed no improvement. Memantine addition to antipsychotic treatment, in schizophrenia patients might improve their clinical status, primarily the negative signs, but not their cognitive deficits. Further research is needed to replicate these observations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Eur Arch Psychiatry Clin Neurosci 2009 Aug 259: 293-7 |
| PMID | 19224106 |
| Title | Association study of clock gene (CLOCK) and schizophrenia and mood disorders in the Japanese population. |
| Abstract | Recently the CLOCK genes have been reported to play some roles in neural transmitter systems, including the dopamine system, as well as to regulate circadian rhythms. Abnormalities in both of these mechanisms are thought to be involved in the pathophysiology of major mental illness such as schizophrenia and mood disorders including bipolar disorder (BP) and major depressive disorder (MDD). Recent genetic studies have reported that CLOCK, one of the CLOCK genes, is associated with these psychiatric disorders. Therefore, we investigated the association between the six tagging SNPs in CLOCK and the risk of these psychiatric disorders in Japanese patients diagnosed with schizophrenia (733 patients), BP (149) and MDD (324), plus 795 Japanese controls. Only one association, with schizophrenia in females, was detected in the haplotype analysis (P = 0.0362). However, this significance did not remain after Bonferroni correction (P = 0.0724). No significant association was found with BP and MDD. In conclusion, we suggest that CLOCK may not play a major role in the pathophysiology of Japanese schizophrenia, BP and MDD patients. However, it will be important to replicate and confirm these findings in other independent studies using large samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Fa Yi Xue Za Zhi 2009 Jun 25: 208-11 |
| PMID | 19697782 |
| Title | [Advanced investigation of testamentary capacity of the mentally disordered]. |
| Abstract | Testamentary capacity is one of the civil competences, it means that a natural person enjoys the capacity or qualification to establish testament and deal with his property. Recently, the cases of testamentary capacity assessment of the mentally disordered are increasing. This article firstly introduces the concepts of the testament as well as the testamentary capacity, and then summarizes the assessment standard of the testamentary capacity, by using the Banks v. Goodfellow case as a basis to make the standard criteria including: the understanding of the nature of a will and codicil, the knowledge of the general extent of one's assets, the knowledge of the natural object of one's bounty, the understanding of the impact of the distribution of the assets of the estate, and the absence of a delusion specifically affecting the distribution of the estate. The impact factors of the testamentary capacity, including dementia, mood disorder, schizophrenia, alcohol, drug, and undue influence, etc., are summarized. Lastly, the related assessment tools such as the Mini-Mental State Examination, the CLOCK-Drawing Test, and the Testament Definition Scale are introduced briefly. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Recent Pat CNS Drug Discov 2009 Jan 4: 61-9 |
| PMID | 19149715 |
| Title | The role of melatonin in the immuno-neuro-psychology of mental disorders. |
| Abstract | Melatonin (N-acetyl-5-methoxytryptamine) is a molecule known to be produced in multiple cells and organs. It acts at the level of the biological CLOCK, the suprachiasmatic nuclei, to modulate their activity, thereby influencing circadian rhythms, and also sleep processes. The clinical application of melatonin in the treatment of human mental disorders is still in its infancy. Until now, melatonin only has been used in psychiatry because of its hypnotic, resynchronizing and antioxidant actions. In this review, we hypothesized that melatonin might play an important role as an adjuvant therapy, in mental disturbances, due to other properties including its anti-inflammatory, antinociceptive, anxiolytic, drug detoxification properties, protective actions against osteoporosis, etc. Complex interactions occur between the brain and the immune system and currently is accepted that psychological and psychiatric illness can compromise immune and hormonal functions. Altered psychological states often influence the susceptibility of an individual to illness or modify the course of the illness and its prognosis. The present review discusses on the advantages of the co-treatment with melatonin and recent patents in three major psychiatric disorders: depression, bipolar syndrome and schizophrenia. The findings suggest new vistas in both the pathophysiology and the pharmacology of mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Isr J Psychiatry Relat Sci 2010 -1 47: 27-35 |
| PMID | 20686197 |
| Title | Circadian rhythms and clock genes in psychotic disorders. |
| Abstract | Numerous lines of evidence suggest that a disordered circadian system contributes to the etiology and symptomatology of major psychiatric disorders. Sleep disturbances, particularly rapid eye movement (REM) sleep, have been observed in bipolar affective disorder (BPD) and schizophrenia. Therapies aimed at altering the timing and duration of sleep and realigning circadian rhythms, including sleep scheduling, wake extension, light therapy and drug therapies that alter sleep and circadian rhythms appear beneficial for affective disorders. Interventional studies aiming to correct sleep and circadian disturbances in schizophrenia are scarce, although exogenous melatonin has been shown to improve both sleep structure and psychotic symptoms. The study of molecular CLOCK mechanisms in psychiatric disorders is also gaining interest. Genetics studies have found associations with CLOCK, PERIOD1, PERIOD3, and TIMELESS in schizophrenia. Most research on BPD has focused on polymorphisms of CLOCK, but the lithium target GSK-3 may also be significant. New research examining the role of circadian rhythms and CLOCK genes in major mental illness is likely to produce rapid advances in circadian-based therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Am J Geriatr Psychiatry 2010 Oct 18: 908-16 |
| PMID | 20808150 |
| Title | Comparing the influences of age and disease on distortion in the clock drawing test in Japanese patients with schizophrenia. |
| Abstract | The CLOCK Drawing Test (CDT) is commonly used for cognitive screening, but there are few studies that compare performance on the CDT among schizophrenic patients of different ages. The objective of this study was to investigate the influence of schizophrenia and aging on performance in the CDT. schizophrenic patients (N = 244) and a comparison group (N = 875) were recruited as subjects. Freedman's CDT was completed by all subjects, and the influences of disease and aging on performance in the CDT were examined. Multiple comparisons of the CDT scores between patients and the comparison group and within three age subgroups (young: less than 40 years, middle aged: 40-59 years, elderly: more than 60 years) were performed. There was a significant interaction of diagnosis and age, and the education significantly influenced the total score for all CDT conditions. For almost all age subgroups of patients, individuals with schizophrenia had significantly lower scores on all the CDT conditions than did the comparison group subjects. For patients and the comparison group, the elderly subgroup performed significantly worse than the young and middle-aged subgroups on almost all conditions of the CDT. Qualitative analysis of the CLOCKs drawn revealed that the number of CDT categories in which schizophrenic patients scored significantly lower than the comparison group tended to increase with aging across both groups. This study suggests that performance on the CDT was impaired not only by disease but also by aging. The study confirms that the CDT is sensitive enough to screen for cognitive impairments in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Am J Geriatr Psychiatry 2010 Oct 18: 908-16 |
| PMID | 20808150 |
| Title | Comparing the influences of age and disease on distortion in the clock drawing test in Japanese patients with schizophrenia. |
| Abstract | The CLOCK Drawing Test (CDT) is commonly used for cognitive screening, but there are few studies that compare performance on the CDT among schizophrenic patients of different ages. The objective of this study was to investigate the influence of schizophrenia and aging on performance in the CDT. schizophrenic patients (N = 244) and a comparison group (N = 875) were recruited as subjects. Freedman's CDT was completed by all subjects, and the influences of disease and aging on performance in the CDT were examined. Multiple comparisons of the CDT scores between patients and the comparison group and within three age subgroups (young: less than 40 years, middle aged: 40-59 years, elderly: more than 60 years) were performed. There was a significant interaction of diagnosis and age, and the education significantly influenced the total score for all CDT conditions. For almost all age subgroups of patients, individuals with schizophrenia had significantly lower scores on all the CDT conditions than did the comparison group subjects. For patients and the comparison group, the elderly subgroup performed significantly worse than the young and middle-aged subgroups on almost all conditions of the CDT. Qualitative analysis of the CLOCKs drawn revealed that the number of CDT categories in which schizophrenic patients scored significantly lower than the comparison group tended to increase with aging across both groups. This study suggests that performance on the CDT was impaired not only by disease but also by aging. The study confirms that the CDT is sensitive enough to screen for cognitive impairments in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | J. Biol. Rhythms 2011 Aug 26: 305-13 |
| PMID | 21775289 |
| Title | Interval timing is intact in arrhythmic Cry1/Cry2-deficient mice. |
| Abstract | Localizing the self in time is fundamental for daily life functioning and is lacking in severe disabling neuropsychiatric disorders like schizophrenia. Brains keep track of time across an impressive range of scales. Great progress has been made in identifying the molecular machinery of the circadian CLOCK, the brain's master CLOCK that operates on the 24-hour scale and allows animals to know the "time of the day" that important events occur, without referring to external cues. However, the biology of interval timing, the mechanism responsible for durations in the seconds-to-minutes-to-hours range, remains a mystery, and an obvious question is whether there is a common biological solution for keeping track of time across these 2 time scales. To address this, we trained Cry1/Cry2 double knockout mice on an interval timing task with durations that ranged between 3 and 27 seconds. The mice were kept under constant light conditions to avoid any exogenously induced form of daily rhythmicity. We observed that the homozygous knockouts displayed as accurate and precise a temporal memory as the control mice. This suggests that the Cry1 and Cry2 genes are not an important component of the interval timer. Furthermore, proper calibration of the interval timer does not depend on a functional circadian CLOCK. Thus, these 2 timing systems likely rely on different and independent biological mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Schizophr. Res. 2011 Feb 125: 187-93 |
| PMID | 21050724 |
| Title | Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs. |
| Abstract | In the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in CLOCK genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics. To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the CLOCK pathway, and two genes of downstream hormone receptors. Clinical parameters were evaluated in 261 patients with schizophrenia spectrum disorder. Polymorphisms in LEPR, MC3R, NR3C1, PER2 and SDC3 were genotyped. In order to control for multiple testing, permutation tests were used to generate corrected empirical p-values using the Max(T) procedure in PLINK. A significant effect of the rs6196 polymorphism in the NR3C1 on weight (?=-4.18; SE=2.02; p=0.018), BMI (?=-1.88; SE=0.64; p=0.004), waist (?=-5.77; SE=1.75; p=0.001) and waist/hip ratio (?=-0.03; SE=0.012; p=0.009) was found. Permutation tests confirmed the findings for BMI (p=0.037) and waist (p=0.024). Carriers of the G allele consistently displayed better parameters than patients with the wild type allele. A weak effect of rs4949184 in SDC3 on BMI was found, but this did not sustain permutation testing (?=-1.27; SE=0.58; p=0.030, p=0.270 after permutations). Variations in genes implicated in circadian regulation or its related downstream pathways may be important in the regulation of antropomorphic parameters in patients with schizophrenia during long-term treatment with SGA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | J. Neurosci. 2011 Jun 31: 9658-64 |
| PMID | 21715631 |
| Title | Is gamma-band activity in the local field potential of V1 cortex a "clock" or filtered noise? |
| Abstract | Gamma-band (25-90 Hz) peaks in local field potential (LFP) power spectra are present throughout the cerebral cortex and have been related to perception, attention, memory, and disorders (e.g., schizophrenia and autism). It has been theorized that gamma oscillations provide a "CLOCK" for precise temporal encoding and "binding" of signals about stimulus features across brain regions. For gamma to function as a CLOCK, it must be autocoherent: phase and frequency conserved over a period of time. We computed phase and frequency trajectories of gamma-band bursts, using time-frequency analysis of LFPs recorded in macaque primary visual cortex (V1) during visual stimulation. The data were compared with simulations of random networks and CLOCK signals in noise. Gamma-band bursts in LFP data were statistically indistinguishable from those found in filtered broadband noise. Therefore, V1 LFP data did not contain CLOCK-like gamma-band signals. We consider possible functions for stochastic gamma-band activity, such as a synchronizing pulse signal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Mol. Biol. Rep. 2011 Jan 38: 349-54 |
| PMID | 20364331 |
| Title | The association of CLOCK gene T3111C polymorphism and hPER3 gene 54-nucleotide repeat polymorphism with Chinese Han people schizophrenics. |
| Abstract | Many reports have shown that the biologic rhythm could be altered due to mutations of circadian gene hCLOCK or hPeriod, and the mutations of circadian genes have some relationship with psychosis according to recent studies. A preliminary study has been conducted to examine wether the T3111C single nucleotide polymorphism of the hCLOCK gene or the length polymorphism of the hPer3 gene is associated with the development of schizophrenia. The samples from schizophrenics (n=148, male: 57.4%, female: 42.6%) and normal controls (n=199, male: 59.3%, female: 40.7%) were examined. Allele frequencies of T3111C SNP of hCLOCK were significantly different between schizophrenics and controls (?2=19.738, P<0.05). schizophrenics had a significantly higher frequency of the C allele compared with controls (OR=2.613, 95% CI=1.693-4.034). On the other hand, there is no significant difference of allele frequencies of 18 exon of hper3 between schizophrenics and controls (?2=0.192, P>0.05). Our results suggest that the T3111C (RS1801260) polymorphism of hCLOCK gene is associated with schizophrenia, but it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. It is important to address of the relationship between circadian gene polymorphisms and dopamine functions in further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Mol. Biol. Rep. 2011 Jan 38: 349-54 |
| PMID | 20364331 |
| Title | The association of CLOCK gene T3111C polymorphism and hPER3 gene 54-nucleotide repeat polymorphism with Chinese Han people schizophrenics. |
| Abstract | Many reports have shown that the biologic rhythm could be altered due to mutations of circadian gene hCLOCK or hPeriod, and the mutations of circadian genes have some relationship with psychosis according to recent studies. A preliminary study has been conducted to examine wether the T3111C single nucleotide polymorphism of the hCLOCK gene or the length polymorphism of the hPer3 gene is associated with the development of schizophrenia. The samples from schizophrenics (n=148, male: 57.4%, female: 42.6%) and normal controls (n=199, male: 59.3%, female: 40.7%) were examined. Allele frequencies of T3111C SNP of hCLOCK were significantly different between schizophrenics and controls (?2=19.738, P<0.05). schizophrenics had a significantly higher frequency of the C allele compared with controls (OR=2.613, 95% CI=1.693-4.034). On the other hand, there is no significant difference of allele frequencies of 18 exon of hper3 between schizophrenics and controls (?2=0.192, P>0.05). Our results suggest that the T3111C (RS1801260) polymorphism of hCLOCK gene is associated with schizophrenia, but it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. It is important to address of the relationship between circadian gene polymorphisms and dopamine functions in further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Hum Psychopharmacol 2011 Oct 26: 445-50 |
| PMID | 21882241 |
| Title | No significant association between SIRT1 gene and methamphetamine-induced psychosis in the Japanese population. |
| Abstract | We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the CLOCK genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype) ?=?0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype) ?=?0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p?=?0.146). Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Schizophr. Res. 2011 Mar 126: 20-7 |
| PMID | 21112189 |
| Title | Sense of agency is altered in patients with a putative psychotic prodrome. |
| Abstract | Sense of agency (SoAg)--the experience of controlling one's own actions and their consequences--has been studied in schizophrenia but not in the earlier stages of the disease, i.e. in patients with a putative psychotic prodrome (PP). Previous research has shown that time judgments of voluntary actions can provide an implicit measure of the SoAg. 30 PP patients and 30 healthy controls performed voluntary key presses while watching a rotating CLOCK hand on a monitor. After each key press they had to estimate the time of the action (based on the perceived position of the CLOCK hand at the time of the key press). By varying the probability with which the simple manual action was followed by a tone, we investigated whether shifts in perceptual estimates of the operant action towards a resulting effect depended on the actual occurrence of the effect (retrospective process) or on the prediction that the effect will occur. PP patients differed from healthy controls but their results did not resemble previous findings in schizophrenia patients. PP patients showed numerically--but not significantly--stronger temporal linkage between action and consequence than healthy controls. Retrospective and predictive influences on action binding were stronger in PP patients. Furthermore, the altered influence of prediction was significantly correlated to ego-psychopathology. Distortions of agency constitute a core feature of the disease that is already present in the PP but may evolve further with progression of the illness. Distortions of agency may thus represent a promising additional predictive risk factor for transition to psychosis in PP patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Genes Brain Behav. 2011 Apr 10: 257-63 |
| PMID | 20977650 |
| Title | SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study. |
| Abstract | Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian CLOCK system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the ?(2) test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P(all markers) = 4.89 × 10(-15)). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Neurosci. Lett. 2012 Oct 529: 66-9 |
| PMID | 22981886 |
| Title | An evaluation of polymorphisms in casein kinase 1 delta and epsilon genes in major psychiatric disorders. |
| Abstract | Disturbances of the circadian rhythm are involved in the pathophysiology of bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). Specifically, because CLOCK gene dysfunction is good candidate for enhancing the susceptibility to these psychiatric disorders, we selected two circadian rhythm-related genes (CSNK1D and CSNK1E) and investigated genetic associations of the genes with these three disorders. None of the SNPs showed a significant association with MDD, but a SNP (rs2075984) in CSNK1E and SNP (rs6502097) in CSNK1D were associated with SCZ (P=0.0091, uncorrected) and BD (P=0.030, uncorrected), respectively. To confirm these findings, we analyzed an independent dataset (maximum N=3815) but found a lack of association (P=0.63 for rs2075984 and P=0.61 for rs6502097). The final meta-analysis showed no association between these SNPs with SCZ (P=0.21) and BD (P=0.53). These results do not support that genetic variation in CSNK1D and CSNK1E is a susceptibility factor for major psychiatric disorders in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Schizophr. Res. 2012 Mar 135: 51-4 |
| PMID | 22260961 |
| Title | A ticking clock for the production of sequential actions: where does the problem lie in schizophrenia? |
| Abstract | schizophrenia has been associated to a distorted time CLOCK. By subtracting contact duration from Inter Response Interval, we report evidence for preserved internal CLOCK in schizophrenia, with normal spontaneous tapping tempo. Contact durations were however increased in patients suggesting a specific problem in the fast integration of incoming haptic feedback with outgoing motor efferences. This integration deficit would emerge at an early phase, since Ultra High Risk patients also revealed abnormal tapping stability. Tactile screens revealed to be a simple and low cost apparatus that may constitute a suitable measuring kit for the characterisation of sensory motor deficits in clinical settings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Neuropharmacology 2012 Mar 62: 1221-9 |
| PMID | 21296093 |
| Title | Gene-dose dependent effects of methamphetamine on interval timing in dopamine-transporter knockout mice. |
| Abstract | The dopamine transporter (DAT) is the major regulator of the spatial and temporal resolution of dopaminergic neurotransmission in the brain. Hyperdopaminergic mice with DAT gene deletions were evaluated for their ability to perform duration discriminations in the seconds-to-minutes range. DAT -/- mice were unable to demonstrate temporal control of behavior in either fixed-interval or peak-interval timing procedures, whereas DAT +/- mice were similar to DAT +/+ mice under normal conditions. Low to moderate-dose methamphetamine (MAP) challenges indicated that DAT +/- mice were less sensitive to the CLOCK-speed enhancing effects of MAP compared with DAT +/+ mice. In contrast, DAT +/- mice were more vulnerable than DAT +/+ mice to the disruptive effects of MAP at high doses as revealed by the elevation of response rate in the right hand tail of the Gaussian-shaped timing functions. Moreover, this treatment made DAT +/- mice functionally equivalent to DAT -/- mice in terms of the loss of temporal control. Taken together, these results demonstrate the importance of dopaminergic control of interval timing in cortico-striatal circuits and the potential link of timing dysfunctions to schizophrenia and drug abuse. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Psychiatry Res 2012 May 197: 13-8 |
| PMID | 22497958 |
| Title | Impaired predictive timing with spared time interval production in individual with schizophrenia. |
| Abstract | There is evidence for timing dysfunctions in schizophrenia. However, few studies have evaluated the processing of intervals in the hundreds of milliseconds range, despite their role in the timing of speech, music and movements. This study looked into the prediction and estimation mechanisms for intervals in that time range in individuals with schizophrenia and age-matched neurotypical controls. Specifically, we questioned the capacity of the patients to detect a phase shift that requires the processing of a deviation from 'what should happen when' given prior event regularity. The minimum detectable phase shift was estimated from an adaptive staircase procedure with or without the need for sensorimotor synchronization. Results revealed that patients were significantly impaired relative to controls, at each of the tested inter-onset intervals (IOI=300, 600 and 900ms). A control experiment used the method of repeated interval production to show that both groups performed similarly in the production of target intervals (T=500ms and 1000ms). We conclude that schizophrenia is associated with predictive timing deficits, which cannot be attributed directly to a faster or slower running internal CLOCK. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Eur Arch Psychiatry Clin Neurosci 2012 Apr 262: 199-205 |
| PMID | 22120873 |
| Title | Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. |
| Abstract | The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Curr. Biol. 2012 Feb 22: 314-9 |
| PMID | 22264613 |
| Title | Disrupted circadian rhythms in a mouse model of schizophrenia. |
| Abstract | Sleep and circadian rhythm disruption has been widely observed in neuropsychiatric disorders including schizophrenia [1] and often precedes related symptoms [2]. However, mechanistic basis for this association remains unknown. Therefore, we investigated the circadian phenotype of blind-drunk (Bdr), a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes modulated by prenatal factors and reversible by antipsychotic treatment [3, 4]. Notably, SNAP-25 has been implicated in schizophrenia from genetic [5-8], pathological [9-13], and functional studies [14-16]. We show here that the rest and activity rhythms of Bdr mice are phase advanced and fragmented under a light/dark cycle, reminiscent of the disturbed sleep patterns observed in schizophrenia. Retinal inputs appear normal in mutants, and CLOCK gene rhythms within the suprachiasmatic nucleus (SCN) are normally phased both in vitro and in vivo. However, the 24 hr rhythms of arginine vasopressin within the SCN and plasma corticosterone are both markedly phase advanced in Bdr mice. We suggest that the Bdr circadian phenotype arises from a disruption of synaptic connectivity within the SCN that alters critical output signals. Collectively, our data provide a link between disruption of circadian activity cycles and synaptic dysfunction in a model of neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Neurobiol. Dis. 2012 Jan 45: 145-55 |
| PMID | 21820053 |
| Title | The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington's disease. |
| Abstract | A progressive disintegration of the rest-activity rhythm has been observed in the R6/2 mouse model of Huntington's disease (HD). Rest-activity rhythm is controlled by a circadian CLOCK located in the suprachiasmatic nuclei (SCN) of the hypothalamus, although SCN-independent oscillators such as the methamphetamine (MAP)-sensitive circadian oscillator (MASCO) can also control rhythmicity, even in SCN-lesioned animals. We aimed to test whether or not the administration of MAP could restore a normal rest-activity rhythm in R6/2 mice, via the activation of the MASCO. We administered chronic low doses of MAP to wild-type (WT) and presymptomatic (7-8 weeks) R6/2 mice, in constant darkness. As expected, ~40% of the WT mice expressed a rest-activity rhythm controlled by the MASCO, with a period of around 32 h. By contrast, the MASCO was missing from almost 95% of the R6/2 mice, even at early stages of disease. Interestingly, although the MASCO was deficient, initially MAP was able to stabilize the day/night activity ratio in R6/2 mice and delay the onset of disintegration of the rest-activity rhythm driven by the SCN. Furthermore, in presymptomatic R6/2 mice treated with L-DOPA, a MASCO-like component began to emerge, although this never became established. Our data show a major dysfunction of the MASCO in presymptomatic R6/2 mice that is likely to be due to an early abnormality of the catecholaminergic systems. We suggest that the dysfunction of the MASCO in humans could be partially responsible for circadian disturbances observed in HD patients, as well as patients with other neurological diseases in which both catecholaminergic and circadian abnormalities are present, such as Parkinson's disease and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Clin Psychopharmacol Neurosci 2012 Apr 10: 1-12 |
| PMID | 23429436 |
| Title | Are cardiometabolic and endocrine abnormalities linked to sleep difficulties in schizophrenia? A hypothesis driven review. |
| Abstract | schizophrenia is a psychiatric disorder that includes symptoms such as hallucinations, disordered thoughts, disorganized or catatonic behaviour, cognitive dysfunction and sleep-wake disturbance. In addition to these symptoms, cardiometabolic dysfunction is common in patients with schizophrenia. While previously it has been thought that cardiometabolic symptoms in patients with schizophrenia were associated with medications used to manage this disorder, more recently it has been demonstrated that these symptoms are present in drug naive and unmedicated patients. Sleep-wake disturbance, resulting in chronic sleep loss has also been demonstrated to induce changes in cardiometabolic function. Chronic sleep loss has been associated with an increased risk for weight gain, obesity and cardiac and metabolic disorders, independent of other potentially contributing factors, such as smoking and body mass index. We hypothesise that the sleep-wake disturbance comorbid with schizophrenia may play a significant role in the high prevalence of cardiometabolic dysfunction observed in this patient population. Here we present a critical review of the evidence that supports this hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Psychiatry Res 2012 Dec 200: 159-66 |
| PMID | 22862910 |
| Title | Time perception disorders are related to working memory impairment in schizophrenia. |
| Abstract | Time perception (TP) impairment in schizophrenia has been originally described by clinicians and afterwards addressed in laboratory. Previous studies generally observed that schizophrenia patients overestimate time and that their timing sensitivity is impaired. However, because of the disease cognitive impairments, no study until now allows to draw definitive conclusions about the nature of TP disturbances. The aim of this study is to isolate a genuine TP disorder in schizophrenia, i.e., a disorder that would be related to the functioning of an internal CLOCK. The main hypothesis tested is that patients' internal CLOCK runs faster than that of healthy controls. Twenty-five patients suffering from a first-episode of schizophrenia and twenty-five healthy controls performed an innovative task called method of dynamic stimuli, designed to measure the natural frequency (F(n)) of the internal CLOCK, concomitant with a neuropsychological assessment. We observed no significant difference in F(n) between groups. Compared to controls, there was a marginally higher variability in time reproduction in patients. Patients' pattern of results and significant correlations between TP tasks and memory outcomes suggest that TP impairments are related to memory impairment in schizophrenia. These conclusions are supported by a growing literature showing that cognition is involved in TP in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | J Neural Transm (Vienna) 2012 Oct 119: 1097-104 |
| PMID | 22669264 |
| Title | The role of sleep problems and circadian clock genes in childhood psychiatric disorders. |
| Abstract | CLOCK gene research and the analysis of circadian rhythmicity on the behavioural, cellular and molecular level are increasingly contributing to accumulate clinically relevant knowledge in the fields of neuroscience, psychopharmacology and adult psychiatry. However, the role of circadian phenomena, including sleep alterations in mental disorders during childhood and adolescence remains largely enigmatic. Fortunately, recent publications have addressed this problem and there is now some evidence available highlighting the relevance of CLOCK genes in conditions, such as ADHD, mood disorders, schizophrenia and anxiety disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Transl Psychiatry 2012 -1 2: e73 |
| PMID | 22832735 |
| Title | A promoter polymorphism in the Per3 gene is associated with alcohol and stress response. |
| Abstract | The period homolog genes Per1, Per2 and Per3 are important components of the circadian CLOCK system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Br J Psychiatry 2012 Apr 200: 308-16 |
| PMID | 22194182 |
| Title | Sleep and circadian rhythm disruption in schizophrenia. |
| Abstract | Sleep disturbances comparable with insomnia occur in up to 80% of people with schizophrenia, but very little is known about the contribution of circadian coordination to these prevalent disruptions. A systematic exploration of circadian time patterns in individuals with schizophrenia with recurrent sleep disruption. We examined the relationship between sleep-wake activity, recorded actigraphically over 6 weeks, along with ambient light exposure and simultaneous circadian CLOCK timing, by collecting weekly 48 h profiles of a urinary metabolite of melatonin in 20 out-patients with schizophrenia and 21 healthy control individuals matched for age, gender and being unemployed. Significant sleep/circadian disruption occurred in all the participants with schizophrenia. Half these individuals showed severe circadian misalignment ranging from phase-advance/delay to non-24 h periods in sleep-wake and melatonin cycles, and the other half showed patterns from excessive sleep to highly irregular and fragmented sleep epochs but with normally timed melatonin production. Severe circadian sleep/wake disruptions exist despite stability in mood, mental state and newer antipsychotic treatment. They cannot be explained by the individuals' level of everyday function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Brain 2012 Mar 135: 656-77 |
| PMID | 21921020 |
| Title | Pathophysiological distortions in time perception and timed performance. |
| Abstract | Distortions in time perception and timed performance are presented by a number of different neurological and psychiatric conditions (e.g. Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder and autism). As a consequence, the primary focus of this review is on factors that define or produce systematic changes in the attention, CLOCK, memory and decision stages of temporal processing as originally defined by Scalar Expectancy Theory. These findings are used to evaluate the Striatal Beat Frequency Theory, which is a neurobiological model of interval timing based upon the coincidence detection of oscillatory processes in corticostriatal circuits that can be mapped onto the stages of information processing proposed by Scalar Timing Theory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | PLoS ONE 2012 -1 7: e32091 |
| PMID | 22384149 |
| Title | A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. |
| Abstract | Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian "CLOCK genes" associated with BD. However, no significant CLOCK gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the CLOCK is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the CLOCK gene network at three levels: essential "core" CLOCK genes, upstream circadian CLOCK modulators, and downstream CLOCK controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of CLOCK vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core CLOCK genes but not among upstream CLOCK modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic CLOCK-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between CLOCK genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Psychogeriatrics 2012 Dec 12: 242-7 |
| PMID | 23279146 |
| Title | Neuropsychological and functional correlates of clock-drawing test in elderly institutionalized patients with schizophrenia. |
| Abstract | There has been a growing need for a cognitive assessment tool that can be used for older adults with schizophrenia in clinical settings. The CLOCK-drawing test (CDT) is a brief cognitive test that covers a wide range of cognitive function. Although it is widely used to assess patients with dementia, limited data are available on its usefulness in older patients with schizophrenia. Thus, we investigated the psychometric properties of the CDT and their relationship with life functions to examine the test's usefulness for assessing cognitive function in older adults with schizophrenia. Seventy-three older adults with chronic schizophrenia who had been hospitalized for over 1 year participated in the study. We adopted the executive CLOCK-drawing task for administration and scoring of the CDT, which consists of free-drawn and copy conditions. The Mini-Mental State Examination and the Brief Assessment of Cognition in schizophrenia were administered. Symptom severity and life functions were assessed with the Positive and Negative Syndrome Scale and the Life Skills Profile, respectively. Both free-drawn and copy scores significantly correlated with the Mini-Mental State Examination score and the Brief Assessment of Cognition in schizophrenia composite score. These scores also significantly correlated with symptom severity and length of current hospitalization. Stepwise regression analysis showed that only the copy score, together with symptom severity, predicted the Life Skills Profile score. The CDT can assess cognitive function in older adults with schizophrenia. Moreover, CDT performance is associated with life functions independent from other clinical variables. These results suggest that the CDT is a useful cognitive assessment tool for this population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Ann Gen Psychiatry 2012 -1 11: 20 |
| PMID | 22827835 |
| Title | Reducing treatment delay for early intervention: evaluation of a community based crisis helpline. |
| Abstract | A limited number of studies have assessed the pathways to care of patients experiencing psychosis for the first time. Helpline/clinic programs may offer patients who are still functional but have potential for crisis an alternative that is free from judgment. In this study we report on patient calling a round-the-CLOCK crisis helpline for suicide prevention supported by psychiatric facilities in Mumbai, India. Chi-square and test of mean differences were used to compare outcomes between first-episode patients and those with a previous history. Within five years, the helpline received 15,169 calls. Of those callers, 2341 (15.4%) experienced suicidal ideation. Two hundred and thirty four patients opting for counseling lasting 12?months agreed to a psychiatric assessment. Of those, 32 were fist time psychosis sufferers, whereas, 54 had previously been psychotic. Of all psychiatric assessments, the clinic received 94 patients with 'first-episode psychosis'. We found that the duration of illness was significantly shorter (17 vs. 28?months) and suicide attempts were fewer (16 vs. 21) in first-time psychosis sufferers compared to those with a treatment history. We conclude that some first-episode patients of schizophrenia and other disorders do access services by using helplines. We also argue that helplines may be somewhat immune to stigma, allowing patients a safe alternative when finding help. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Curr. Biol. 2012 Feb 22: 314-9 |
| PMID | 22264613 |
| Title | Disrupted circadian rhythms in a mouse model of schizophrenia. |
| Abstract | Sleep and circadian rhythm disruption has been widely observed in neuropsychiatric disorders including schizophrenia [1] and often precedes related symptoms [2]. However, mechanistic basis for this association remains unknown. Therefore, we investigated the circadian phenotype of blind-drunk (Bdr), a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes modulated by prenatal factors and reversible by antipsychotic treatment [3, 4]. Notably, SNAP-25 has been implicated in schizophrenia from genetic [5-8], pathological [9-13], and functional studies [14-16]. We show here that the rest and activity rhythms of Bdr mice are phase advanced and fragmented under a light/dark cycle, reminiscent of the disturbed sleep patterns observed in schizophrenia. Retinal inputs appear normal in mutants, and CLOCK gene rhythms within the suprachiasmatic nucleus (SCN) are normally phased both in vitro and in vivo. However, the 24 hr rhythms of arginine vasopressin within the SCN and plasma corticosterone are both markedly phase advanced in Bdr mice. We suggest that the Bdr circadian phenotype arises from a disruption of synaptic connectivity within the SCN that alters critical output signals. Collectively, our data provide a link between disruption of circadian activity cycles and synaptic dysfunction in a model of neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | In Silico Pharmacol 2013 -1 1: 15 |
| PMID | 25505659 |
| Title | Comparison of gene expression profiles in the blood, hippocampus and prefrontal cortex of rats. |
| Abstract | The comparability of gene expression between blood and brain tissues is a central issue in neuropsychiatric research where the analysis of molecular mechanisms in the brain is of high importance for the understanding of the diseases and the discovery of biomarkers. However, the accessibility of brain tissue is limited. Therefore, knowledge about how easily accessible peripheral tissue, e. g. blood, is comparable to and reflects gene expression of brain regions will help to advance neuropsychiatric research. Gene expression in the blood, hippocampus (HC) and prefrontal cortex (PFC) of genetically identical rats was compared using a genome-wide Affymetrix gene expression microarray covering 29,215 expressed genes. A total of 56.8% of 15,717 expressed genes were co-expressed in blood and at least one brain tissue, while 55.3% of all genes were co-expressed in all three tissues simultaneously. The overlapping genes included a set of genes of relevance to neuropsychiatric diseases, in particular bipolar disorder, schizophrenia and alcohol addiction. These genes included CLOCK, COMT, FAAH, NPY, NR3C1, NRGN, PBRM1, TCF4, and SYNE. This study provides baseline data on absolute gene expression and differences between gene expression in the blood, HC and PFC brain tissue of genetically identical rats. The present data represents a valuable resource for future studies as it might be used for first information on gene expression levels of genes of interest in blood and brain under baseline conditions. Limitations of our study comprise possible contamination of brain tissue with blood and the non-detection of genes with very low expression levels. Genes that are more highly expressed in the brain than in the blood are of particular interest since changes in their expression, e.g. due to disease status, or treatment, are likely to be detected in an experiment. In contrast, genes with higher expression in the blood than in the brain are less informative since their higher baseline levels could superimpose variation in brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Neuropsychobiology 2013 -1 67: 1-5 |
| PMID | 23221812 |
| Title | The CLOCK C3111T polymorphism is associated with reward dependence in healthy Japanese subjects. |
| Abstract | The Circadian Locomotor Output Cycles Kaput (CLOCK) T3111C polymorphism has been associated with several psychiatric disorders, including mood disorders and schizophrenia, which are linked to specific personality traits. We investigated the relationship between the personality traits measured by the Temperament and Character Inventory (TCI) and the C3111T polymorphism of the CLOCK gene in healthy Japanese subjects. The sample population contained 1,092 healthy subjects (age = 27.4 ± 8.7 years) who completed the TCI. Genomic DNA was isolated from whole blood and genotyped using the TaqMan allele-specific assay method. The associations between the gene polymorphisms and TCI scores were evaluated by one-way analysis of variance and multiple regression analysis. We also compared the TCI scores between the C allele carrier (C/T and C/C genotypes) and non-carrier (T/T genotype) groups using Student's t test. Males and females were analyzed separately. There was no significant association between the C3111T genotype and any TCI score, but multiple regression analyses revealed significant but opposite associations between reward dependence and the C3111T polymorphism in males and females (p = 0.032, ? = 0.087 and p = 0.05, ? = -0.087, respectively). Similarly, when we compared the TCI scores of CLOCK C3111T C carrier and non-carrier subjects, we found that male C allele carriers had significantly higher reward dependence scores than non-carriers (p = 0.02). Our findings suggest that the CLOCK C3111T polymorphism may affect personality traits in healthy Japanese subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Neuroimage 2013 Nov 88C: 61-68 |
| PMID | 24246490 |
| Title | Prediction of individual season of birth using MRI. |
| Abstract | Previous research suggests statistical associations between season of birth (SOB) with prevalence of neurobehavioral disorders such as schizophrenia and bipolar disorder, personality traits such as novelty and sensation seeking, and suicidal behavior. These effects are thought to be mediated by seasonal differences in perinatal photoperiod, which was recently shown to imprint circadian CLOCK neurons and behavior in rodents. However, it is unknown whether SOB is associated with any measurable differences in the normal human adult brain, and whether individual SOB can be deduced based on phenotype. Here I show that SOB predicts morphological differences in brain structure, and that MRI scans carry spatially distributed information allowing significantly above chance prediction of an individual's SOB. Using an open source database of over 550 structural brain scans, Voxel-Based Morphometry (VBM) analysis showed a significant SOB effect in the left superior temporal gyrus (STG) in males (p=0.009, FWE whole-brain corrected), with greater gray matter volumes in fall and winter births. A cosinor analysis revealed a significant annual periodicity in the left STG gray matter volume (Zero Amplitude Test: p<5×10(-7)), with a peak towards the end of December and a nadir towards the end of June, suggesting that perinatal photoperiod accounts for this SOB effect. Whole-brain VBM maps were used as input features to multivariate machine-learning based analyses to classify SOB. Significantly greater than chance prediction was achieved in females (overall accuracy 35%, p<0.001), but not in males (overall accuracy 26%, p=0.45). Pairwise binary classification in females revealed that the highest discrimination was obtained for winter vs. summer classification (peak area under the ROC curve=0.71, p<0.0005). Discriminating regions included fusiform and middle temporal gyrus, inferior and superior parietal lobe, cerebellum, and dorsolateral and dorsomedial prefrontal cortex. Results indicate that SOB is detectable with MRI, imply that SOB exerts effects on the developing human brain that persist through adulthood, and suggest that neuroimaging may be a valuable intermediate phenotype in bridging the gap between SOB and personality and neurobehavioral disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | PLoS ONE 2013 -1 8: e67615 |
| PMID | 23826328 |
| Title | Impaired Representation of Time in Schizophrenia Is Linked to Positive Symptoms and Cognitive Demand. |
| Abstract | Time processing critically relies on the mesencephalic dopamine system and striato-prefrontal projections and has thus been suggested to play a key role in schizophrenia. Previous studies have provided evidence for an acceleration of the internal CLOCK in schizophrenia that may be linked to dopaminergic pathology. The present study aimed to assess the relationship between altered time processing in schizophrenia and symptom manifestation in 22 patients and 22 controls. Subjects were required to estimate the time needed for a visual stimulus to complete a horizontal movement towards a target position on trials of varying cognitive demand. It was hypothesized that patients - compared to controls - would be less accurate at estimating the movement time, and that this effect would be modulated by symptom manifestation and task difficulty. In line with the notion of an accelerated internal CLOCK due to dopaminergic dysregulation, particularly patients with severe positive symptoms were expected to underestimate movement time. However, if altered time perception in schizophrenia was better explained in terms of cognitive deficits, patients with severe negative symptoms should be specifically impaired, while generally, task performance should correlate with measures of processing speed and cognitive flexibility. Patients underestimated movement time on more demanding trials, although there was no link to disease-related cognitive dysfunction. Task performance was modulated by symptom manifestation. Impaired estimation of movement time was significantly correlated with PANSS positive symptom scores, with higher positive symptom scores associated with stronger underestimation of movement time. The present data thus support the notion of a deficit in anticipatory and predictive mechanisms in schizophrenia that is modulated both by symptom manifestation and by cognitive demand. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Psychopharmacology (Berl.) 2013 Jan 225: 453-60 |
| PMID | 22885914 |
| Title | Differential effects of antipsychotics on lateral bias and social attention in female rats. |
| Abstract | Prior research has demonstrated that individuals with schizophrenia may exhibit lateral biases in attention and deficits in social behavior. The use of a noninvasive animal model of attentional impairments in schizophrenia and antipsychotic drugs can help elucidate the biological underpinnings of attentional processes and facilitate the study of novel therapeutics. The purpose of this study was to compare the effects of three antipsychotic drugs on measures of lateral bias and social attention in healthy, unoperated female rats. Female Long-Evans rats selected for a preexisting lateral bias in attention, a right behavioral orientation preference (BOP), were administered clozapine, haloperidol, sulpiride, or vehicle. Lateral bias in attention was assessed by determining which forelimb rats removed a nuisance stimulus from first. Social attention was examined by comparing the latency to remove nuisance stimuli in the presence of a social (inaccessible female rat) versus non-social (blinking CLOCK) distractor. All antipsychotic drugs eliminated right lateral bias in attention, while control animals retained their initial bias. Clozapine eliminated right lateral bias more rapidly than the other drugs. Animals receiving clozapine also selectively displayed increased attention to another rat. The results suggest that the antipsychotic medication clozapine rapidly alters attentional bias and uniquely influences attention to a social stimulus. The right BOP paradigm is a useful animal model for comparing antipsychotic drug effects on lateralized attentional bias and attention to social stimuli. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Hum Psychopharmacol 2014 Jul 29: 336-41 |
| PMID | 25163438 |
| Title | Polymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatment. |
| Abstract | Clozapine-induced sialorrhea (CIS) is a common, inconvenient and socially stigmatizing adverse effect. The pathophysiology of CIS may be related to the effect of clozapine on the muscarinic and adrenergic receptors as well as the disruption of the circadian rhythms. The aim of this study was to find out if polymorphisms in muscarinic M1 and M3 receptor genes (CHRM1 and CHRM3), adrenoceptor alpha 2A gene (ADRA2A) or CLOCK circadian regulator gene (CLOCK) are associated with CIS. Two hundred and thirty-seven clozapine-treated Finnish schizophrenia patients were genotyped for CHRM1, CHRM3, CLOCK and ADRA2A polymorphisms, and their salivary dysfunction was assessed with two questions. Twenty-six of these patients had previously been on medication to treat CIS. Comparisons of the genotypes between patients with excessive versus non-excessive salivation were analysed. Genotype distributions between patients and control group and haplotypes were also studied. CHRM1, CHRM3 and CLOCK polymorphisms and haplotypes were not associated with CIS. ADRA2A (rs1800544) genotype was associated with CIS (p?=?0.029). In patients with CIS, CC genotype (n?=?103) was more common than in G-allele carriers (n?=?79) (p?=?0.013, OR 2.13, 95% CI: 1.17-3.88). No differences were found in the distributions of genotypes between patients and controls. ADRA2A genotype was associated with CIS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Ann Neurosci 2014 Oct 21: 138-43 |
| PMID | 25452674 |
| Title | Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample. |
| Abstract | Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Curr Psychiatry Rep 2014 Oct 16: 483 |
| PMID | 25135782 |
| Title | Circadian clock and stress interactions in the molecular biology of psychiatric disorders. |
| Abstract | Many psychiatric disorders are characterized by circadian rhythm abnormalities, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian "CLOCK genes" commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors, further supporting the idea of a connection between the circadian CLOCK and psychiatric disorders. However, if circadian CLOCK dysfunction is a common risk factor for multiple psychiatric disorders, it is unknown if and how these putative CLOCK abnormalities could be expressed differently, and contribute to multiple, distinct phenotypes. One possible explanation is that the circadian CLOCK modulates the biological responses to stressful environmental factors that vary with an individual's experience. It is known that the circadian CLOCK and the stress response systems are closely related: Circadian CLOCK genes regulate the physiological sensitivity to and rhythmic release of glucocorticoids (GC). In turn, GCs have reciprocal effects on the CLOCK. Since stressful life events or increased vulnerability to stress are risk factors for multiple psychiatric disorders, including post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), alcohol use disorder (AUD) and schizophrenia (SCZ), we propose that modulation of the stress response is a common mechanism by which circadian CLOCK genes affect these illnesses. Presently, we review how molecular components of the circadian CLOCK may contribute to these six psychiatric disorders, and present the hypothesis that modulation of the stress response may constitute a common mechanism by which the circadian CLOCK affects multiple psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Neuropsychiatr Dis Treat 2014 -1 10: 2325-30 |
| PMID | 25525361 |
| Title | Association of Per3 length polymorphism with bipolar I disorder and schizophrenia. |
| Abstract | Sleep-wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India. Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers. An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08-2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (? (2)=4.634; P<0.03) than in the control group. No significant association was observed in the allele frequencies of four and five repeat alleles in schizophrenia patients when compared with controls. The occurrence of the five repeat allele of Per3 may be a risk factor for BD-I onset in this ethnic group. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Chronobiol. Int. 2014 Aug 31: 838-44 |
| PMID | 24824748 |
| Title | Association between restless legs syndrome and CLOCK and NPAS2 gene polymorphisms in schizophrenia. |
| Abstract | Previous studies have suggested that there is a genetic basis to restless legs syndrome (RLS) development. Occurrence of antipsychotic-induced RLS could also be due to differences in genetic susceptibility. We investigated whether CLOCK and NPAS2 gene polymorphisms are associated with RLS in schizophrenic patients on antipsychotics because RLS symptoms usually manifest during the evening and night. We assessed symptoms of RLS in 190 Korean schizophrenic patients on antipsychotics and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria: (i) subjects who met all the criteria and (ii) the remaining subjects who did not meet all the criteria. We found a significant difference in the number of subjects with different genotype and allele carrier frequencies for the CLOCK gene (rs2412646) between the two groups (p?=?0.031 and 0.010, respectively). Distribution of CLOCK haplotypes (rs2412646-rs1801260) was significantly different between schizophrenic patients with and without RLS (p?=?0.021). However, the distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. Our results suggest that CLOCK polymorphisms are associated with increased susceptibility of schizophrenic patients to RLS. We hypothesize that RLS in schizophrenia patients treated with antipsychotics may be a very mild akathisia that manifests during the night and is under control of circadian oscillation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | PLoS ONE 2014 -1 9: e110310 |
| PMID | 25340473 |
| Title | Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders. |
| Abstract | Increasing evidence suggests that CLOCK genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and CLOCK genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular CLOCK including SHARP1 and SHARP2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | Behav. Neurosci. 2014 Aug 128: 468-73 |
| PMID | 24865659 |
| Title | Enhanced extinction of contextual fear conditioning in Clock?19 mutant mice. |
| Abstract | CLOCK genes have been implicated in several disorders, such as schizophrenia, bipolar disorder, autism spectrum disorders, and drug dependence. However, few studies to date have examined the role of CLOCK genes in fear-related behaviors. The authors used mice with the CLOCK?19 mutation to assess the involvement of this gene in contextual fear conditioning. Male wild-type (WT) and CLOCK?19 mutant mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by daily 12-min retention trials. There were no differences between mutant and WT mice in the acquisition of contextual fear, and WT and mutant mice demonstrated similar freezing during the first retention session. However, extinction of contextual fear was accelerated in mutant mice across the remaining retention sessions, as compared to WT mice, suggesting a role for CLOCK in extinction following aversive learning. Because the CLOCK?19 mutation has previously been demonstrated to result in an increase in dopamine signaling, the authors confirmed the role of dopamine in extinction learning using preretention session administration of a low dose of the dopamine transport reuptake inhibitor modafinil (0.75 mg/kg), which resulted in decreased freezing across retention sessions. These findings are consistent with an emerging portrayal of the importance of CLOCK genes in noncircadian functions, as well as the important role of dopamine in extinction learning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 71 | Annu Rev Psychol 2014 -1 65: 743-71 |
| PMID | 24050187 |
| Title | Properties of the internal clock: first- and second-order principles of subjective time. |
| Abstract | Humans share with other animals an ability to measure the passage of physical time and subjectively experience a sense of time passing. Subjective time has hallmark qualities, akin to other senses, which can be accounted for by formal, psychological, and neurobiological models of the internal CLOCK. These include first-order principles, such as changes in CLOCK speed and how temporal memories are stored, and second-order principles, including timescale invariance, multisensory integration, rhythmical structure, and attentional time-sharing. Within these principles there are both typical individual differences--influences of emotionality, thought speed, and psychoactive drugs--and atypical differences in individuals affected with certain clinical disorders (e.g., autism, Parkinson's disease, and schizophrenia). This review summarizes recent behavioral and neurobiological findings and provides a theoretical framework for considering how changes in the properties of the internal CLOCK impact time perception and other psychological domains. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 72 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Apr 165B: 254-60 |
| PMID | 24687905 |
| Title | Testing the role of circadian genes in conferring risk for psychiatric disorders. |
| Abstract | Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian CLOCK genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular CLOCK influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of P?CLOCK genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells. Our results suggest that genes encoding components of the molecular CLOCK are not good candidates for harboring common variants that increase risk to bipolar disorder, schizophrenia, or major depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 73 | Genome Biol. 2014 -1 15: 499 |
| PMID | 25358694 |
| Title | Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders. |
| Abstract | The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases,including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude. We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions. Our results suggest that human populations adapted to life at different latitudes by tuning their circadian CLOCK systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 74 | Front Psychol 2014 -1 5: 816 |
| PMID | 25136321 |
| Title | Processing of sub- and supra-second intervals in the primate brain results from the calibration of neuronal oscillators via sensory, motor, and feedback processes. |
| Abstract | The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular CLOCKs, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by "neural temporal unit," defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active CLOCK is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 75 | Neuropsychiatr Dis Treat 2014 -1 10: 2325-30 |
| PMID | 25525361 |
| Title | Association of Per3 length polymorphism with bipolar I disorder and schizophrenia. |
| Abstract | Sleep-wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India. Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers. An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08-2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (? (2)=4.634; P<0.03) than in the control group. No significant association was observed in the allele frequencies of four and five repeat alleles in schizophrenia patients when compared with controls. The occurrence of the five repeat allele of Per3 may be a risk factor for BD-I onset in this ethnic group. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 76 | Int Rev Psychiatry 2014 Apr 26: 139-54 |
| PMID | 24892891 |
| Title | Circadian misalignment and health. |
| Abstract | Circadian rhythms are near 24-h patterns of physiology and behaviour that are present independent of external cues including hormones, body temperature, mood, and sleep propensity. The term 'circadian misalignment' describes a variety of circumstances, such as inappropriately timed sleep and wake, misalignment of sleep/wake with feeding rhythms, or misaligned central and peripheral rhythms. The predominance of early research focused on misalignment of sleep to the biological night. However, discovery of CLOCK genes and the presence of peripheral circadian oscillators have expanded the definitions of misalignment. Experimental studies conducted in animal models and humans have provided evidence of potential mechanisms that link misalignment to negative outcomes. These include dysregulation of feeding behaviours, changes in appetite stimulating hormones, glucose metabolism and mood. This review has two foci: (1) to describe how circadian misalignment has been defined and evaluated in laboratory and field experiments, and (2) to describe evidence linking different types of circadian misalignment to increased risk for physical (cardiovascular disease, diabetes, obesity, cancer) and psychiatric (depression, bipolar, schizophrenia, attention deficit) disorders. This review will describe the role of circadian misalignment as a risk factor for disease in the general population and in clinical populations, including circadian rhythm sleep disorders and psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 77 | Front Behav Neurosci 2014 -1 8: 162 |
| PMID | 24834040 |
| Title | Links between Circadian Rhythms and Psychiatric Disease. |
| Abstract | Determining the cause of psychiatric disorders is a goal of modern neuroscience, and will hopefully lead to the discovery of treatments to either prevent or alleviate the suffering caused by these diseases. One roadblock to attaining this goal is the realization that neuropsychiatric diseases are rarely due to a single gene polymorphism, environmental exposure, or developmental insult. Rather, it is a complex interaction between these various influences that likely leads to the development of clinically relevant syndromes. Our lab is exploring the links between environmental exposures and neurobehavioral function by investigating how disruption of the circadian (daily) CLOCK alters the structure and function of neural circuits, with the hypothesis that disrupting this crucial homeostatic system can directly contribute to altered vulnerability of the organism to other factors that interact to produce psychiatric illness. This review explores some historical and more recent findings that link disrupted circadian CLOCKs to neuropsychiatric disorders, particularly depression, mania, and schizophrenia. We take a comparative approach by exploring the effects observed in human populations, as well as some experimental models used in the laboratory to unravel mechanistic and causal relationships between disruption of the circadian CLOCK and behavioral abnormalities. This is a rich area of research that we predict will contribute greatly to our understanding of how genes, environment, and development interact to modulate an individual's vulnerability to psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 78 | Chronobiol. Int. 2014 Aug 31: 838-44 |
| PMID | 24824748 |
| Title | Association between restless legs syndrome and CLOCK and NPAS2 gene polymorphisms in schizophrenia. |
| Abstract | Previous studies have suggested that there is a genetic basis to restless legs syndrome (RLS) development. Occurrence of antipsychotic-induced RLS could also be due to differences in genetic susceptibility. We investigated whether CLOCK and NPAS2 gene polymorphisms are associated with RLS in schizophrenic patients on antipsychotics because RLS symptoms usually manifest during the evening and night. We assessed symptoms of RLS in 190 Korean schizophrenic patients on antipsychotics and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria: (i) subjects who met all the criteria and (ii) the remaining subjects who did not meet all the criteria. We found a significant difference in the number of subjects with different genotype and allele carrier frequencies for the CLOCK gene (rs2412646) between the two groups (p?=?0.031 and 0.010, respectively). Distribution of CLOCK haplotypes (rs2412646-rs1801260) was significantly different between schizophrenic patients with and without RLS (p?=?0.021). However, the distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. Our results suggest that CLOCK polymorphisms are associated with increased susceptibility of schizophrenic patients to RLS. We hypothesize that RLS in schizophrenia patients treated with antipsychotics may be a very mild akathisia that manifests during the night and is under control of circadian oscillation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 79 | Chronobiol. Int. 2015 Jun 32: 591-5 |
| PMID | 25798540 |
| Title | Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene. |
| Abstract | Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian CLOCK gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p?=?0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 80 | Meth. Enzymol. 2015 -1 552: 325-49 |
| PMID | 25707284 |
| Title | Sleep and circadian rhythm disruption and recognition memory in schizophrenia. |
| Abstract | schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core CLOCK genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 81 | Behav. Brain Res. 2015 May 284: 58-68 |
| PMID | 25677649 |
| Title | Constant light uncovers behavioral effects of a mutation in the schizophrenia risk gene Dtnbp1 in mice. |
| Abstract | Various psychiatric disorders, including schizophrenia, are comorbid with sleep and circadian rhythm disruptions. To understand the links between circadian rhythms and schizophrenia, we analyzed wheel-running behavior of Sandy (Sdy) mice, which have a loss-of-function mutation in the schizophrenia risk gene Dtnbp1, and exhibit several behavioral features of schizophrenia. While rhythms of Sdy mice were mainly normal under light-dark conditions (LD) or in constant darkness (DD), they had a significantly longer free-running period under constant light (LL) compared to wild-type (WT) littermates. The mutant mice also had a higher subjective day/subjective night ratio of activity under LL, indicating lower amplitude, and a lower precision of their onsets of activity under all three lighting conditions. These observations are reminiscent of the circadian disruptions observed in schizophrenia patients. This prompted us to assess schizophrenia-relevant behavioral abnormalities in Sdy mice following alteration of the circadian rhythms by presentation of constant light. Spontaneous locomotor activity, prepulse inhibition (PPI) of acoustic startle and anxiety-like behavior were assessed under baseline LD conditions, then in LL, and then again in LD. Under LL, the Sdy mice showed significantly increased spontaneous locomotion as well as deficits in PPI compared to WT mice. Strikingly, these behavioral deficits persisted even after the mice were returned in LD conditions. While LL led to an increase in anxiety-like behavior in WT animals that was fully reversed after 3 weeks in LD, this effect was not observed in the Sdy mutants. Overall, these results suggest that Dtnbp1 deficiency may lead to increased vulnerability to schizophrenia under environmental conditions where circadian rhythms are altered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 82 | Psychiatr. Clin. North Am. 2015 Dec 38: 777-92 |
| PMID | 26600108 |
| Title | Sleep Disturbances in Schizophrenia. |
| Abstract | Sleep disturbances are prevalent in patients with schizophrenia and play a critical role in the morbidity and mortality associated with the illness. Subjective and objective assessments of sleep in patients with schizophrenia have identified certain consistent findings. Findings related to the sleep structure abnormalities have shown correlations with important clinical aspects of the illness. Disruption of specific neurotransmitter systems and dysregulation of CLOCK genes may play a role in the pathophysiology of schizophrenia-related sleep disturbances. Antipsychotic medications play an important role in the treatment of sleep disturbances in these patients and have an impact on their sleep structure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 83 | Neuroimage 2015 Oct 119: 316-24 |
| PMID | 26143206 |
| Title | Same clock, different time read-out: Spontaneous brain oscillations and their relationship to deficient coding of cognitive content. |
| Abstract | Neuronal oscillations provide an efficient means of communication, fostering functional neural states supporting action and reaction. High in the action hierarchy, cognitive abilities are severely compromised in neuropsychiatric disease such as schizophrenia. Current thinking highlights a CLOCKing mechanism provided by the phase of an ongoing slow oscillation that offers a temporal frame for coding of perceptual and computational elements. Yet unclear is whether and how a dysregulated CLOCKing mechanism accounts for diminished cognitive performance. Neuromagnetic oscillatory activity was related to cognitive performance assessed by the MATRICS Consensus Cognitive Battery in 58 healthy individuals (HC) and 46 schizophrenia patients (SZ). HC showed a correlation between gamma-band oscillations (>40 Hz) and working memory performance. This relationship was disrupted in several ways in SZ. First, patients evidenced lower gamma power, poorer working memory performance, and no relationship between these measures. Second, the power spectra were dominated by ~10 Hz alpha oscillations with no group differences in amplitude. However, analysis of phase-to-amplitude coupling (PAC) revealed exaggerated CLOCKing of gamma activity by alpha phase in SZ, associated with poor working memory performance. Third, despite entrainment by the same 10 Hz CLOCK, gamma amplitude was abnormally distributed across the duty cycle in SZ, a potential consequence of compromised interneuron inhibition. Fourth, SZ showed over-engagement of a fronto-parietal network measured by gamma phase coherence, suggesting a brain state hindering cognitive output. Such an endogenous temporal organization may be a core dysfunction in SZ: a segregation/integration input imbalance fostering reduced cognitive performance and compromised behavioral output. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 84 | Mol. Psychiatry 2016 Jun 21: 768-85 |
| PMID | 27046645 |
| Title | Towards understanding and predicting suicidality in women: biomarkers and clinical risk assessment. |
| Abstract | Women 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 Keywords | schizophrenia, schizophrenic, schizophrenics |
| 85 | Schizophr. Res. 2016 Apr -1: -1 |
| PMID | 27132483 |
| Title | Altered circadian clock gene expression in patients with schizophrenia. |
| Abstract | Impaired circadian rhythmicity has been reported in several psychiatric disorders. schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the CLOCK genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERB? and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular CLOCK in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 86 | Schizophr. Res. 2016 May -1: -1 |
| PMID | 27236410 |
| Title | Altered CSNK1E, FABP4 and NEFH protein levels in the dorsolateral prefrontal cortex in schizophrenia. |
| Abstract | schizophrenia constitutes a complex disease. Negative and cognitive symptoms are enduring and debilitating components of the disorder, highly associated to disability and burden. Disrupted neurotransmission circuits in dorsolateral prefrontal cortex (DLPFC) have been related to these symptoms. To identify candidates altered in schizophrenia, we performed a pilot proteomic analysis on postmortem human DLPFC tissue from patients with schizophrenia (n=4) and control (n=4) subjects in a pool design using differential isotope peptide labelling followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). We quantified 1315 proteins with two or more unique peptides, 116 of which showed altered changes. Of these altered proteins, we selected four with potential roles on cell signaling, neuronal development and synapse functioning for further validation: casein kinase I isoform epsilon (CSNK1E), fatty acid-binding protein 4 (FABP4), neurofilament triplet H protein (NEFH), and retinal dehydrogenase 1 (ALDH1A1). Immunoblot validation confirmed our proteomic findings of these proteins being decreased in abundance in the schizophrenia samples. Additionally, we conducted immunoblot validation of these candidates on an independent sample cohort comprising 23 patients with chronic schizophrenia and 23 matched controls. In this second cohort, CSNK1E, FABP4 and NEFH were reduced in the schizophrenia group while ALDH1A1 did not significantly change. This study provides evidence indicating these proteins are decreased in schizophrenia: CSNK1E, involved in circadian molecular CLOCK signaling, FABP4 with possible implication in synapse functioning, and NEFH, important for cytoarchitecture organization. Hence, these findings suggest the possible implication of these proteins in the cognitive and/or negative symptoms in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 87 | Transl Psychiatry 2016 -1 6: e802 |
| PMID | 27163203 |
| Title | Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report. |
| Abstract | The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian CLOCK upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian CLOCK) and PIGF and UHMK1 (ubiquitin-mediated proteolysis). Finally, focusing analysis on brain structure volumes revealed significantly lower bilateral hippocampal volumes in MAP subjects. Overall, these results suggest similar molecular and neurocognitive mechanisms underlying the pathophysiology of psychosis and SCZ regardless of substance abuse and provide preliminary evidence supporting the MAP paradigm as an exemplar for SCZ biomarker discovery. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 88 | Nat Commun 2016 -1 7: 10889 |
| PMID | 26955885 |
| Title | Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. |
| Abstract | Our sleep timing preference, or chronotype, is a manifestation of our internal biological CLOCK. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian CLOCK machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 89 | Psychoneuroendocrinology 2016 Feb 64: 108-16 |
| PMID | 26630391 |
| Title | Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients. |
| Abstract | Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of CLOCK genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of CLOCK gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 90 | Curr Top Behav Neurosci 2016 Jan -1: -1 |
| PMID | 26728169 |
| Title | Disrupted Circadian Rhythm as a Common Player in Developmental Models of Neuropsychiatric Disorders. |
| Abstract | The environment in which individuals develop and mature is critical for their physiological and psychological outcome; in particular, the intrauterine environment has reached far more clinical relevance given its potential influence on shaping brain function and thus mental health. Gestational stress and/or maternal infection during pregnancy has been related with an increased incidence of neuropsychiatric disorders, including depression and schizophrenia. In this framework, the use of animal models has allowed a formal and deep investigation of causal determinants. Despite disruption of circadian CLOCKs often represents a hallmark of several neuropsychiatric disorders, the relationship between disruption of brain development and the circadian system has been scarcely investigated. Nowadays, there is an increasing amount of studies suggesting a link between circadian system malfunction, early-life insults and the appearance of neuropsychiatric diseases at adulthood. Here, we briefly review evidence from clinical literature and animal models suggesting that the exposure to prenatal insults, i.e. severe gestational stress or maternal immune activation, changes the foetal hormonal milieu increasing the circulating levels of both glucocorticoids and pro-inflammatory cytokines. These two biological events have been reported to affect genes expression in experimental models and critically interfere with brain development triggering and/or exacerbating behavioural anomalies in the offspring. Herein, we highlight the importance to unravel the individual components of the body circadian system that might also be altered by prenatal insults and that may be causally associated with the disruption of neural and endocrine developmental programming. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |