Laboratory of Pathophysiology of Psychiatric Diseases Center for Psychiatry & Neurosciences INSERM, U894, University Paris Descartes 2 ter rue d'Alésia, 75014 Paris, France Tel: 00 33 1 40 78 86 25
Abstract: The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high risk' versus 'low risk' alleles in cases with dependence versus controls. Studies were analyzed by random-effects meta-analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta-analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of ⥠16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I2 = 85%). In line with the polygenic model, our meta-analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well-phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.
Abstract: Background: Adult rats exposed to methylazoxymethanol (MAM) at embryonic day
17 (E17) consistently display behavioral characteristics similar to that observed in patients
with schizophrenia and replicate neuropathological findings from the prefrontal cortex of
psychotic individuals. However, a systematic neuropathological analysis of the hippocampal
formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein
consistently associated with schizophrenia and potentially involved in the mechanism of
action of MAM, participates in the neuropathological effects of this compound. Therefore, a
thorough assessment including cytoarchitectural and neuromorphometric measurements of
eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression
and methylation levels were also studied.
Principal Findings: Compared to untreated rats, MAM-exposed animals showed a
reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus
associated with decreased neuronal soma. The entorhinal cortex also showed laminar
disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased
whereas reelin positive neurons and reelin expression were unchanged.
Conclusions: Our results indicate that E17-MAM exposure reproduces findings from
the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while
providing little support for reelinâs involvement. Moreover, these results strongly suggest
MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite
formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.
Abstract: Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.
Abstract: Inhibition of return (IOR) is a phenomenon thought to reflect a mechanism to protect the organism from redirecting attention to previously scanned insignificant locations. A number of studies reported altered IOR in schizophrenia patients with a reduction of its amplitude. However, incomplete sampling of stimulus onset asynchronies (SOAs) makes data on IOR time course incomplete. We examined 14 stabilized young patients with recent onset schizophrenia and 16 healthy controls matched for gender, age, and years of education. Schizophrenia patients (13 males, 1 female) had a mean age of 26.3±5.8 years, mean number of years of study of 9.6±3.6. Their illness had a mean duration of 147 weeks. Patients displayed moderate overall slow RTs (387 ms) in comparison to controls (322 ms). Onset of IOR was found delayed in schizophrenia patients appearing between 700 and 800 ms following the cue onset while it appeared at 300 ms in controls. In patients, IOR was constant up to 1100 ms, however its amplitude was weak with an average of 6 ms. Validity effects (overall and at each SOA value) were uncorrelated to age, years of study, duration of illness, or PANSS total and subscale scores.
Abstract: Some of the cognitive impairments of schizophrenia are already detectable before the onset of the disease, and could help to identify individuals at higher risk of psychosis. In patients with schizophrenia, semantic verbal fluency (VF) is more impaired than phonological fluency. We investigated whether the same profile is present in young patients at Ultra High Risk of psychosis (UHR). One hundred and fifty six young patients (15â30 y.o.) consecutively seeking help at our specialized youth mental health center with no definite psychiatric diagnoses were recruited and assessed with the CAARMS. Individuals meeting the criteria for UHR were compared to the remaining patients considered as Help Seeker Controls (HSCo). UHR individuals had a lower mean total semantic fluency score than HSCo. This effect was significant for each semantic category (âanimalsâ and âfruitsâ). By contrast, there were no differences in phonological fluency scores between UHR and HSCo either in the total score or when each letter (âPâ and âRâ) was considered separately. Semantic but not phonological VF differentiated UHR individuals from non-psychotic help-seeking young adults. These results suggest that semantic deficits are present during the prodromal phase, prior to clinical expression of full-blown psychosis, and suggest that prodromes could be associated with alteration in temporal brain areas.
Abstract: BACKGROUND: Despite progress in chemo-therapeutics, schizophrenia remains a
chronic disease with occurrence of residual symptoms and drug resistance in 60%
of the cases. Besides, cognitive impairment is frequent and highly correlated to
social dysfunction seen in patients with schizophrenia. Several cognitive
remediation programs have been elaborated. REHACOM is one of such programs. Aim
of the study is to evaluate through a case control the efficiency of REHACOM
towards cognitive functions. METHODS: This program has been administered to a
patient suffering from undifferentiated schizophrenia which was ameliorated after
drug therapy considering positive symptoms but still was complaining from
cognitive deficits causing social withdrawal. RESULTS: After following the
remediation program, the patient was ameliorated considering its negative
symptoms as attested by an amelioration of the PANSS negative score and
considering its cognitive performances on memory, attention and executive
functions. We have also noticed an improvement in his self-esteem and his quality
of life. CONCLUSION: This first trial of a cognitive remediation program among
our patients suffering from schizophrenia using REHACOM was encouraging.
Enlarging its use and designing controlled studies will be the next step of our
study.
Abstract: BACKGROUND: Schizophrenia is characterised by positive and negative symptoms as well as thought disorders and disorganised behaviour. Multiple cognitive deficits within the areas of memory, attention and executive functions are also associated with schizophrenia. Aim of the study was to proceed to a study of correlations between clinical dimensions of schizophrenia and cognitive functions. METHODS: The authors recruited 105 patients suffering from schizophrenia spectrum disorders (DSM IV criteria). The patients were clinically stabilised, showing no depressive state at the time of the study, with no organic brain disorders and no history of drug intake. They were clinically evaluated using the PANSS and the Calgary Depression Scale. A cognitive battery was also administered. RESULTS: Positive dimension of schizophrenia was shown to be independent from any cognitive function. Disorganisation was negatively correlated to attention, working memory, long-term verbal memory and executive functions. Negative dimension was negatively correlated with working memory and executive functions. CONCLUSION: Cognition wasn't correlated to the positive dimension of schizophrenia whereas it was correlated to the negative and to the disorganisation dimension of the disease. This is probably due to overlapping of concepts.
Abstract: BACKGROUND: Cognitive disorders are common and severe in schizophrenia. They are
also correlated with the functional outcome of the disease. Cognition can not be
assessed during a standard clinical interview but needs to be evaluated by means
of specific cognitive tasks. Aim of the study is to construct a battery of
cognitive tests which is adapted to the Tunisian cultural and linguistic context
and to collect normative data in Tunisian Arabic speaking healthy subjects.
METHODS: We have selected and adapted cognitive tests to our socio cultural
context. Then we have proceeded to the administration of these tests within a
group of healthy subjects. RESULTS: the cognitive battery is composed of 7 tests:
the Hopkins Verbal Learning Test, the Token test, the Zazzo test, phonemic
fluency, semantic fluency, visual working memory test and number working memory
test. These tests are presented with their manual of utilisation and their
normative data. CONCLUSION: The Tunisian cognitive battery is believed to permit
a better cognitive assessment of patients suffering from schizophrenia.
Improvement of cognitive impairments in schizophrenia is associated with a better
social and professional integration of these patients.
Abstract: Objective: To review systematically the results of genetic studies investigating associations
between putative susceptibility genes for attention-deficit/hyperactivity disorder (ADHD) and
neuropsychological traits relevant for this disorder.
Data sources: Papers were identified through PubMed database searches and systematically
reviewed.
Data synthesis: Twenty-nine studies examined ten genes (DRD4, DAT1, COMT, DBH,
MAOA, DRD5, ADRA2A, GRIN2A, BDNF, and TPH2) in relation to neuropsychological traits
relevant for ADHD. For DRD4, continuous performance test (CPT) and derived tasks were
the most used tests. Association of high reaction time (RT) variability with the 7-repeat allele
absence appears to be the most consistent result and seems to be specific to ADHD. Speed of
processing, set-shifting and cognitive impulsiveness were less frequently investigated but
seem to be altered in the 7-repeat allele carriers. No effect of genotype was found on response
inhibition (the stop and go/no go tasks). For DAT1, four studies provide conflicting results in
relation to omission and commission errors from CPT and derived tasks. High RT variability
seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity.
The other genes have attracted fewer studies and the reported findings need to be replicated.
Conclusions: Several methodological issues including measurement errors, developmental
changes in cognitive abilities, gender, psychostimulant effects, and presence of comorbid
conditions represent confounding factors and may explain conflicting results.
Abstract: BACKGROUND: Memory impairment and verbal learning are the most common cognitive
deficits associated with schizophrenia. Hopkins Verbal Learning Test (HVLT) is
considered to be the most reliable test to asses memory and verbal learning in
this mental illness. AIMS: to create one form of the HVLT which would suit our
linguistic and cultural context and to study the characteristics of this test in
a group of healthy subjects. METHODS: The HVLT consists of a list of 12 words
belonging to 3 semantic categories and which are read orally to the subject with
an immediate and differed recall. The first part of this work was to select words
from a lexical database in order to create the list of the HVLT. The test was
then administered to 103 subjects aged from 17- to 45-years-old (mean=27,4; SD
=7,3) and having between 1 and 20 years of education ( mean=12,2; SD=5,3).
RESULTS: No statistical difference was found within performances of the HVLT
across gender and sex. Whereas, years of education was found to have an impact on
performances. Although statistically difference was found across level of
education. CONCLUSION: Our study permitted us to create one form of the HVLT
which well suits our Tunisian context and which we could use to evaluate memory
functions among people suffering from schizophrenia.
Abstract: Objective: Attention-deficit/hyperactivity disorder (ADHD) is often associated with reduced IQ and
high levels of externalizing behavior (EB). This study tested if DRD4 7-repeat allele and DAT1 10-
repeat allele homzygosity interact in modulating correlations between IQ and EB in affected boys.
Methods: Boys (n = 130) between 6 and 12 years of age diagnosed with ADHD were included in the
study. IQ and EB were assessed by WISC-III and Child Behavioral Checklist, respectively. The 40bp
variable number tandem repeat (VNTR) of the DAT1 gene and the 48bp VNTR of the DRD4 gene
polymorphisms were genotyped and 4 subgroups were defined by the presence/absence of the DRD4
7-repeat allele and by the presence/absence of the DAT1 10/10 genotype. Correlation coefficients were
compared using the Fisherâs Z transformation and regression lines by a Potthoff analysis.
Results: In the total sample, all correlation coefficients between EB score and IQ were non significant.
Also, no differences in IQ were observed between the 4 genotype groups. However, different pattern
of correlations between IQ and EB score appeared. In boys carrying no or only one genetic risk, IQ
and EB score were uncorrelated while in children carrying both risk factors, negative and significant
correlations emerged. Notably, correlation of EB to verbal IQ was strong (r = -0.71) and highly
significant (P < 0.01) in boys carrying both risk alleles. All pair-wise comparisons of correlation
coefficients were significant for EB â verbal IQ correlation. Test of coincidence of regression lines did
not show significant differences.
Conclusions: A specific domain of IQ, namely the verbal quotient is highly correlated to the level of
EB in boys with ADHD carrying both dopaminergic risk genotypes. Further investigations are
required to replicate these results and determine specificity to ADHD.
Abstract: BACKGROUND: Attention is a complex function which matches environment's
information to the needs of the organism. AIMS: describe the different variety of
attention, the attentionnel tests and attentional disorders in the psychiatric
pathology. METHODS: review of literature on PUBMED. RESULTS: There are several
types of attention such as selective attention, sustained attention and the
divided attentions. Besides these different varieties of attention, we find the
pre attentive phenomena: alertness and orientation which leads to preparing the
attention. The investigation of attention requires different tools of measures
such as the Stroop test, the Continuous performance test or the "test de Barrage
de zazzo" and a few years ago the visual detection task of Posner and the
attentional network test that explores the three attentional networks
independently. In psychiatric illness, the attentional disorders are not specific
although certain abnormalities are more suggestive of some pathology like the
disengagement deficit in schizophrenia and the attention deficit and
hyperactivity of children. CONCLUSION: There are several types of attention and
pre attentive phenomena which investigation require specific cognitive tests.
Abstract: Background
Despite a huge well-documented literature on cognitive deficits in schizophrenia, little is known about the own perception of patients regarding their cognitive functioning. The purpose of our study was to create a scale to collect subjective cognitive complaints of patients suffering from schizophrenia with Tunisian Arabic dialect as mother tongue and to proceed to a validation study of this scale.
Methods
The authors constructed the Self-Assessment Scale of Cognitive Complaints in Schizophrenia (SASCCS) based on a questionnaire covering five cognitive domains which are the most frequently reported in the literature to be impaired in schizophrenia. The scale consisted of 21 likert-type questions dealing with memory, attention, executive functions, language and praxia. In a second time, the authors proceeded to the study of psychometric qualities of the scale among 105 patients suffering from schizophrenia spectrum disorders (based on DSM- IV criteria). Patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Global Assessment Functioning Scale (GAF scale) and the Calgary Depression Scale (CDS).
Results
The scale's reliability was proven to be good through Cronbach alpha coefficient equal to 0.85 and showing its good internal consistency. The intra-class correlation coefficient at 11 weeks was equal to 0.77 suggesting a good stability over time. Principal component analysis with Oblimin rotation was performed and yielded to six factors accounting for 58.28 % of the total variance of the scale.
Conclusion
Given the good psychometric properties that have been revealed in this study, the SASCCS seems to be reliable to measure schizophrenic patients' perception of their own cognitive impairment. This kind of evaluation can't substitute for objective measures of cognitive performances in schizophrenia. The purpose of such an evaluation is to permit to the patient to express his own well-being and satisfaction of quality of life.
Abstract: INTRODUCTION: Working memory refers to a limited capacity system for temporary storage and processing of information that is known to depend on the integrity of the prefrontal cortex. It has been classically described as composed of a "central executive" that performs control, selection and planning functions, and two "slave" systems: on the one hand, the phonological loop that holds verbal, speech-based representations, and on the other hand, the visuospatial sketchpad that manipulates spatial and object visual representations. LITERATURE FINDINGS: Studies in schizophrenia have used different tasks that tap different processes within the working memory. Despite the variety of measures, there is solid neuropsychological evidence that patients with schizophrenia demonstrate deficits in all subsystems of working memory. Several studies have shown no correlations between working memory deficits and age, gender, premorbid IQ, duration of disease or positive syndrome, but a correlation has been found with a low-educational level, and negative and disorganization symptoms. Neuroimaging studies have provided evidence of an involvement of the dorsolateral-prefrontal cortex during working memory performance. Many studies have demonstrated a functional deficit in this area. However, several recent studies have reported either equal or increased activation of the dorsolateral-prefrontal cortex in schizophrenia during working memory performance. Working memory deficits are present early in the course of schizophrenia and they have been shown to be consistently associated with reduced levels of elementary social skills and learning capacity. Unaffected relatives of individuals with schizophrenia and individuals diagnosed with schizotypal personality demonstrate deficits in tasks designed to measure working memory function. Working memory dysfunctions might be suitable candidate markers for vulnerability. Certain executive sub-processes seem to be the most heritable component of the working memory. Working memory deficits in schizophrenia may benefit from specific stimulation of receptors such as the dopaminergic D1 receptor, adrenergic alpha-2A receptor or nicotinic receptors. Few studies on the effect of antipsychotic medication on working memory in schizophrenia have been carried out and their results are highly variable. Atypical antipsychotic drugs, notably risperidone, have appeared to improve performance in working memory tasks. Cognitive exercises can improve working memory with a six-month persistent effect.
Abstract: The aim of this study was to examine whether executive deficits underlie positive, negative and disorganisation of schizophrenia. The sample comprised 34 patients (30 males, 4 females) diagnosed with DSM-IV criteria (mean age = 35 ± 9.5 years; mean duration of illness since first psychotic symptoms = 10.2 ± 7 years; mean years of education = 11.7 ± 2.6). Evaluation of patients was performed after achieved sufficient remission (clinically stable for 4 weeks at least, no depressive symptoms at moment of cognitive testing and no medication change during the three last weeks). Symptom dimensions were evaluated using items drawn from the Positive And Negative Symptoms Scale (PANSS). The Negative factor comprised N1 (blunted affect), N2 (emotional withdrawal), N3 (poor contact), N4 (passive, apathetic), N6 (lack of spontaneity), G7 (stereotyped thinking) and G16 (active social avoidance). The Positive factor comprised P1 (delusions), P3 (hallucinatory behaviour), P5 (grandiosity), P6 (suspiciousness) and G9 (unusual thought content). The Disorganisation factor comprised P2 (conceptual disorganisation), N5 (difficulty in abstract thinking), G10 (disorientation) and G11 (poor attention). The mean total PANSS score was 63.3 ± 16 (mean of positive score = 14.3 ± 4.7; mean of negative score = 18.1 ± 6.3; mean of general score = 30.9 ± 8.5). Executive functions were examined through the Wisconsin Card Sorting Test (WCST), the Hayling Test (Tunisian version) and two semantic verbal fluency tasks (simple with one category âanimalsâ and alternating with two categories âfruits and clothesâ). Partial correlations between syndrome scores and cognitive scores were examined while holding the effects of other symptoms, age and education level constant. Severity of disorganisation symptoms correlated with high number of perseverative errors (r = 0.47, P < 0.05) and total errors in the WCST (r = 0.37, P < 0.05) and with reduced score of alternating semantic verbal fluency (r = â0.39, P < 0.05). Severity of both negative and positive dimensions uncorrelated with performance of any of the executive tasks. Also, scores of the Hayling Test (time part B minus time part A; errors part B) and semantic simple verbal fluency (total of correct words) were uncorrelated with symptoms. The present study provides evidence that disorganisation dimension of the PANSS correlates specifically with impaired cognitive flexibility as reflected by high number of perseveration in the WCST and reduced set-shifting in semantic alternating verbal fluency.
Abstract: INTRODUCTION: Most visual environments contain more information than the human brain can process in real time. To overcome this limitation, the attention system acts as a filter by selectively orienting attention to specific regions of the visual field. This ability to orient attention can be reflected in covert shift processes of attention. LITERATURE FINDINGS: In a typical covert orienting task, subjects have to maintain fixation on a central cross and respond as quickly as possible to a target, which appears in a peripheral box following a cue that summons attention to the direction where the target is going to appear (valid cueing) or to the contralateral direction (invalid cueing). When the cues are nonpredictive, the response characteristics critically depend on stimulus-onset asynchrony (SOA). With short SOAs (<300ms), valid cues result in a reaction time advantage over invalid trials, which is due to a reflexive shift of attention towards the source of stimulation. In contrast, with longer SOAs, valid cues result in longer reaction times to the subsequent target. DISCUSSION: This phenomenon is known as the inhibition of return and is mostly thought to reflect an inhibitory mechanism protecting the organism from redirecting attention to previously scanned insignificant locations. Many studies have reported blunted or delayed inhibition of return in patients with schizophrenia. However, some authors reported normal amounts of inhibition of return. This can be partly explained by the use of manipulations of the covert orienting of the attention paradigm that is known to enhance the course of inhibition of return. CONCLUSION: The deficit of inhibition of return seems to be time-stable and to be unrelated to psychopathology or length of illness. The contribution of neuroleptic medication to this deficit cannot be determined. Recent data suggest a deficit of inhibition of return in two human models of psychosis (dimethyltryptamine and ketamine). Further studies should clarify whether blunted inhibition of return might represent a trait marker of schizophrenia.
Abstract: Minor physical anomalies are slight dysmorphic features representing subtle alterations in the development of various bodily structures in the mouth, eye, ear, head, hand, and feet areas. The aim of this study was to assess the frequency and the type of minor physical anomalies in patients with schizophrenia in a Tunisian population. One hundred adult patients (67 men, 33 women, mean age : 38 years (S.D = 10.6), mean age of onset : 24.1 years (S.D = 6.5), educational level : 8 years (S.D = 4.7)) and 143 comparison subjects (95 men, 48 women); mean age : 42.8 years (S.D = 16.6), educational level: 5.7 years (S.D = 4.7) were assessed by using Gourion's scale which consists of 41 minor physical anomalies. The total score in patients with schizophrenia (mean: 1.7, S.D = 1.34) was significantly high than in healthy subjects (mean : 1.2, S.D = 1.06). The cut-off score that optimally discriminated the patients from comparison subjects (maximizing sensitivity and specificity for schizophrenia) was two or more. A score of two or more classified 51% of the patients and 64.3% of the comparison subjects. A higher rate of minor physical anomalies was more specific and rare. Patients showed a higher rate for 20 anomalies, the differences reaching statistical significance for six of them : asymmetric ears (Patients: 5%, Controls: 0%), curved fifth finger (Patients: 7%, Controls: 0.7%), syndactily (Patients: 5%, Controls: 0%), gap between first and second toe (Patients: 12%, Controls : 2.1%), overlapping toes (Patients: 8%, Controls: 1.4%) and asymmetric feet (Patients: 7%, Controls: 0.7%). Nine anomalies were less frequent in patients and only one reached statistical significance : palate anomalies (Patients: 7%, Controls: 17.5%). Twelve anomalies were absent in both groups (large nose basis, facial asymmetry, ptosis, coloboma, low seated ears, furrowed tongue, cleft lip, abnormal palm creases, overlapping fingers, small fingernails, asymmetric hands and hyper-convex toenails). The total score was significantly correlated with the age of onset (R = â0.21, P = 0.03) but not with illness severity (CGI score and number of hospital admissions / duration of illness). Reviewing results of similar studies in other populations, Tunisian patients with schizophrenia seem to have fewer minor physical anomalies. Only three significant frequent anomalies were concordant with results of one another study (curved fifth finger, syndactily and gap between 1st and 2nd toe). This large heterogeneity might be explained by ethnic variability. More studies are needed.
