One-year mirror-image study of the impact of olanzapine long-acting injection on healthcare resource utilization and costs in severe schizophrenia.

Olanzapine long-acting injections (OLAIs) are often prescribed to patients with severe schizophrenia who are typically excluded from randomized clinical trials. To date, no mirror-image study has examined the impact of OLAIs on healthcare resource utilizations in these patients. We conducted a retrospective, one-year mirror-image study of OLAIs on 40 patients with severe schizophrenic disorder. Illness severity was defined by failure to respond to two sequential antipsychotics. Outcomes included: (i) healthcare resource utilizations via hospitalization admissions, bed days, outpatient visits, and inpatient service costs computations (ii) clinical efficacy through changes in the Brief Psychiatric Rating Scale (BPRS) and in the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), and (iii) adverse effects. After one year, OLAIs were associated with significant decreases of 65.7%, 86.2% and 86.2% in hospitalization admissions, bed days, and inpatient service costs respectively. A significant mean change of -0.47 and -0.63 was determined the BPRS and the CGI-SCH scores, respectively. There were no significant differences in the number of outpatient visits and adverse effects, except for post-injection sedation/delirium syndrome whose incidence was 0.30% per injection. This mirror-image study provides the first evidence that prescribing OLAIs reduces in a cost-effective manner average bed days and hospital admissions in patients with severe schizophrenia.

The C'JAAD: a French team for early intervention in psychosis in Paris.

AIM: The aim is to describe a centre operating in Paris that pioneers the early intervention for young people at the onset and at high risk of psychosis in France. METHODS: Comprehensive descriptive analysis of different clinical and service measures is used in describing the implementation of the C'JAAD (Evaluation Centre for Young Adults and Adolescents) using data from an ongoing prospective non-interventional research programme. RESULTS: Over a 2-year period, 151 patients were referred to the C'JAAD and included in the ICAAR research programme. After evaluation by the Comprehensive Assessment of the At-Risk Mental States Scale, 53.7% were identified at risk of developing a psychosis, 20.6% presented a full-blown psychosis and 25.7% were considered not at risk of developing a psychosis. A total of 84% of the at-risk subjects suffered from a psychiatric co-morbidity, of which anxiodepressive symptoms being the most frequent (39%). The global functioning of these at-risk subjects was seriously impaired (average Social and Occupational Functioning Assessment Scale score = 48.9). More than one third of the patients was self-referred (33.8%), 22.5% were addressed by a psychiatrist whereas 10.6% were referred by a general practitioner. CONCLUSIONS: In this paper, we report for the first time the activities of the C'JAAD, the pioneer unit in France for early detection and treatment of young adults with early psychosis. These observations indicate that such early intervention centre is a feasible and sustainable extension of traditional care for people with mental disorders in this country and offers promising perspective for the development of further centres.

Theory of mind and schizophrenia in young and middle-aged patients: Influence of executive functions.

Theory of Mind (ToM) is compromised in schizophrenia, and responsible for social disability. We aim to study the correlation between ToM deficits and Executive Functions (EF), using the Faux Pas Test (FPT) for ToM evaluation, Behavioral Assessment of the Dysexecutive Syndrome (BADS) and Wisconsin Card Sorting Test (WCST) for EF assessment. Two groups of patients with schizophrenia were included: 22 young (18-35 years-old) and 18 middle-aged (>50 years-old) Patients, compared to age-matched Controls. We found worst FPT performances in both groups of patients, but with a more generalized pattern of dysfunction in the middle-aged patient group. This group had worse EF scores than both controls and younger patients. The association of EF with FPT items was uneven. In young patients only empathy (Q6) remained significant after controlling for EF and level of education, while in middle-aged patients faux pas explanation (Q4), false belief (Q5) and total scores remained significant. In young patients only affective TOM was impaired. No correlation was found with clinical symptoms, nor age at onset of the disease. We conclude that ToM deficit arises early during the course of the illness (already present in young patients), increases in middle-aged patients, and relates only partially with EF.

Cognitive control deficit in patients with first-episode schizophrenia is associated with complex deviations of early brain development.

BACKGROUND: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia. METHODS: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement. RESULTS: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology (p = 0.041) as well as interactions between NSS and ACC morphology (p = 0.005), between NSS and handedness (p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume (p = 0.005) on CC measured using the TMT-B score - the TMT-A score. LIMITATIONS: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis. CONCLUSION: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

Cognitive control deficit in patients with first-episode schizophrenia is associated with complex deviations of early brain development.

BACKGROUND: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia. METHODS: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement. RESULTS: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology (p = 0.041) as well as interactions between NSS and ACC morphology (p = 0.005), between NSS and handedness (p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume (p = 0.005) on CC measured using the TMT-B score - the TMT-A score. LIMITATIONS: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis. CONCLUSION: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

The number of past manic episodes is the best predictor of antidepressant-emergent manic switch in a cohort of bipolar depressed patients.

The present study sought to identify factors associated with the onset of a manic or hypomanic episode during the month following a new antidepressant therapy in depressed bipolar patients. Patients receiving mood stabilizers for ≥3 months were screened from 400 French centers and were assessed for a 4-week period following prescription of a first or a new antidepressant. Of the 1242 included participants, 4.8% (n=60) experienced antidepressant-emergent manic switch (AEMS). AEMS was more frequently associated with lifetime manic, depressive, and total mood episodes, and with past AEMS. A higher score at two items of the Montgomery-Åsberg Depression Rating Scale (pessimistic and suicidal thoughts) were significantly associated with AEMS. Logistic regression analysis showed that the number of lifetime manic episodes and past AEMS were the two most factors associated with an AEMS. Having more than four past manic episodes was associated with a 2.84 fold increased risk of AEMS. Cumulative number of past mood episodes seems to be the most important factor for switching to a manic episode following antidepressants in patients with bipolar disorder. Longer-term studies are required to further delineate antidepressant causality from natural disease course.

Major mental disorders, gender, and criminological circumstances of homicide.

OBJECTIVE: To examine the criminological circumstances of homicide in a group of French murderers with and without major mental disorders (MMD) stratified by the perpetrator's gender. METHODS: Sociodemographic, clinical, and criminological variables were collected from the psychiatric expert reports of 210 cases of homicide heard at the High Court of Angers, France. Murderers were categorized according to MMD diagnosis and gender. RESULTS: Among 210 murderers, 17.6% (n = 37) had a MMD (20% of the female perpetrators). Logistic regression models showed that being a murderer with a MMD was associated with younger age (adjusted Odds Ratio OR = 1.03, P = 0.034), high school education (OR = 2.48, P = 0.036), previous use of psychiatric services (OR = 4.75, P = 0.003), alcohol intoxication (OR = 2.71, P = 0.027), and delusional state (OR = 3.96, P = 0.002) at the time of the homicide. Multiple correspondence analyses showed that female murderers with a MMD were more prone to have depression and to use drowning as a method than those without a MMD, and that male murderers with a MMD more often had a high school education and delusional beliefs at the time of the homicide than those without a MMD. CONCLUSION: Specific profiles of criminological circumstances of homicide could help to explore the risk of homicide in female and male patients with a MMD.

"Who is talking to me?" - Self-other attribution of auditory hallucinations and sulcation of the right temporoparietal junction.

Brain imaging research in schizophrenia has provided a better understanding of the neural basis of auditory hallucinations (AH). Recently, renewed interest in the phenomenology of AH raised questions related to their neural substrates. Hence, the neural basis of AH self/other attribution have yet to be investigated as beliefs regarding the origin of the voices is a cardinal feature of AH phenomenology. As the right temporoparietal junction (TPJ) and the inferior parietal lobule (IPL) play a key role in disentangling the origin of sensory events and in self/other distinction, we tested the hypothesis that the morphology of the IPL/TPJ area may be involved in AH self/other attribution. Magnetic resonance images of 39 right-handed patients with persistent auditory hallucinations and 19 healthy subjects were analyzed with sulcus-based morphometry. AH self-other attribution were found to be associated with the sulcal pattern of the posterior part of the Sylvian fissure, encompassing the IPL/TPJ area. The preference for the attribution of AH to self or to others could be associated with early neurodevelopmental events as the sulcal pattern is determined during fetal life and is stable after birth. Our study also raises basic cognitive questions regarding self-consciousness and suggest that impairments at a pre-reflexive level, leading to hearing his/her thoughts as voices ('I' level or feeling of agency), and a reflexive level leading to attribution belief ('Me' level or judgment of agency) are likely involved in AH.

Cortex morphology in first-episode psychosis patients with neurological soft signs.

Schizophrenia is a complex brain disorder associated with numerous etiological factors and pathophysiological pathways leading to multiple clinical outcomes. Compelling evidence suggests that deviations in neurodevelopmental processes are a major risk factor of schizophrenia. The identification of patients with high neurodevelopmental deviance is an important issue as it could help to identify homogeneous subgroups of patients with similar pathophysiological pathways, a key step to decipher the etiology of this complex condition. Several clinical arguments suggest that schizophrenia patients with Neurological Soft Signs (NSS)--ie, observable defects in motor coordination, motor integration, and sensory integration--would have high neurodevelopmental deviance. Based on the analysis of magnetic resonance imaging of 44 first-episode psychosis patients, we compared the cortex morphology, a marker of brain development, in patients with NSS vs patients with nonsignificant NSS. The cortex morphology was automatically assessed from three-dimensional global sulcal index (g-SI, the ratio between total sulcal area and outer cortex area) and regional sulcal indexes (r-SI, the ratio between the area of pooled labeled sulci and the total outer cortex area). Patients with NSS were found to have a lower g-SI in both hemispheres and a lower r-SI in left dorsolateral prefrontal and right lateral occipital cortices. Exploratory analyses revealed correlations between NSS dimensions and r-SI in distinct cortical areas, including dorsolateral and medial prefrontal cortices, lateral temporal, occipital, superior parietal, and medial parieto-occipital cortices. These findings provide evidence of distinct neurodevelopmental pathways in patients with NSS as compared with patients with nonsignificant NSS.

Suicidal behaviours in affective disorders: a deficit of cognitive inhibition?

OBJECTIVE: Suicide has been related to affective disorders. We hypothesized that suicide could be associated with cognitive inhibition deficit. Our study aimed to systematically review all published articles that examined the relation between cognitive inhibition deficit and suicidal behaviours (that is, suicide attempt or suicidal ideation) in patients with affective disorders. METHOD: We performed an English and French MEDLINE and EMBASE search, ranging from 1970 to 2010, indexed under the MeSH terms of suicide, neuropsychology, neuropsychological tests, and executive function, combined with the following title and abstract terms: neuropsychological functions, executive functioning, and executive performance. RESULTS: Among the 164 selected studies, 9 observational studies met the selection criteria and were included in the final analysis. The number of participants ranged from 57 to 244 (28% to 66%, respectively, were men). Executive dysfunction was more frequently found among patients with suicidal behaviours. In particular, higher cognitive inhibition deficit was observed in depressed subjects with suicide behaviours, compared with depressed subjects without any suicidal behaviour. The results of the meta-analysis showed a higher impairment in inhibition score, according to the number of perseverations in the Wisconsin Card Sorting Test (Cohen d = 0.68) than in inhibition according to the time needed to perform the Trail-Making Test part B (d = 0.01) among patients with suicidal behaviour, compared with patients with no suicidal behaviour. CONCLUSION: This systematic review and meta-analysis showed a positive association between cognitive inhibition deficit and suicide attempts in patients with affective disorders. Future research should examine whether cognitive inhibition deficit precedes the suicidal behaviour.

[Therapeutic education in young patients with schizophrenia]. / Education thérapeutique du jeune patient schizophrène.

There is a specific therapeutic patient education program for young adults suffering from schizophrenic disorders. The aim of this therapeutic education project is the improvement in the treatment of schizophrenic patients as well as continuity of care.

Association of an UCP4 (SLC25A27) haplotype with ultra-resistant schizophrenia.

AIMS: Neuronal uncoupling proteins are involved in the regulation of reactive oxygen species production and intracellular calcium homeostasis, and thus, play a neuroprotective role. In order to explore the potential consequences of neuronal uncoupling proteins variants we examined their association in a sample of Caucasian patients suffering from schizophrenia and phenotyped them according to antipsychotic response. MATERIALS & METHODS: Using a case-control design, we compared the frequencies of 15 genetic variants spanning UCP2, UCP4 and UCP5 in 106 French Caucasian patients suffering from schizophrenia and 127 healthy controls. In addition, patients with schizophrenia who responded to antipsychotic treatment were compared with patients with ultra-resistant schizophrenia (URS). This latter population presented no clinical, social and/or occupational remission despite at least two periods of treatment with conventional or atypical antipsychotic drugs and also with clozapine. RESULTS: There were no differences in the distribution of the respective alleles between URS and responding patients. However, one haplotype spanning UCP4 was found to be significantly under-represented in URS patients. This relationship remained significant after multiple testing corrections. CONCLUSION: Although our sample is of limited size and not representative of schizophrenia as a whole, the association found between the URS group and the UCP4 haplotype is noteworthy as it may influence treatment outcome in schizophrenia.

"Where do auditory hallucinations come from?"--a brain morphometry study of schizophrenia patients with inner or outer space hallucinations.

Auditory verbal hallucinations are a cardinal symptom of schizophrenia. Bleuler and Kraepelin distinguished 2 main classes of hallucinations: hallucinations heard outside the head (outer space, or external, hallucinations) and hallucinations heard inside the head (inner space, or internal, hallucinations). This distinction has been confirmed by recent phenomenological studies that identified 3 independent dimensions in auditory hallucinations: language complexity, self-other misattribution, and spatial location. Brain imaging studies in schizophrenia patients with auditory hallucinations have already investigated language complexity and self-other misattribution, but the neural substrate of hallucination spatial location remains unknown. Magnetic resonance images of 45 right-handed patients with schizophrenia and persistent auditory hallucinations and 20 healthy right-handed subjects were acquired. Two homogeneous subgroups of patients were defined based on the hallucination spatial location: patients with only outer space hallucinations (N=12) and patients with only inner space hallucinations (N=15). Between-group differences were then assessed using 2 complementary brain morphometry approaches: voxel-based morphometry and sulcus-based morphometry. Convergent anatomical differences were detected between the patient subgroups in the right temporoparietal junction (rTPJ). In comparison to healthy subjects, opposite deviations in white matter volumes and sulcus displacements were found in patients with inner space hallucination and patients with outer space hallucination. The current results indicate that spatial location of auditory hallucinations is associated with the rTPJ anatomy, a key region of the "where" auditory pathway. The detected tilt in the sulcal junction suggests deviations during early brain maturation, when the superior temporal sulcus and its anterior terminal branch appear and merge.

[Principles of cognitive remediation in schizophrenia]. / Les principes de la remédiation cognitive dans la schizophrénie.

Cognitive remediation is an innovative psychosocial therapy which can provide a substantial benefit, especially for schizophrenic patients. As its name implies, the aim of cognitive remediation is to restore cognitive functions. Most cognitive domains (attention, memory and executive functions) are impaired in schizophrenia. Remediation therapy must be administered by an expert, and is based on cognitive training on the one hand, and on learning of cognitive strategies on the other hand. With these techniques the patient is better able to solve complex cognitive problems and to apply these new skills to everyday situations. Several techniques are available in France, using either computer-based or paper/pencil approaches. The programs are administered over several months, with one or more sessions per week. Cognitive remediation itself provides only a modest cognitive benefit, which must be enhanced by the adjunction of other therapies such as behavioral therapy, learning of social skills, or a vocational program during the first months of employment.