Prevalence of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the National FACE-SZ Cohort.

BACKGROUND: Extrapyramidal side effects (EPS) have been identified as a complication of antipsychotic treatment. Previous meta-analyses have investigated EPS prevalence and risk factors in randomized clinical trials with highly selected patients, but studies in real-world schizophrenia are missing. OBJECTIVE: To examine the prevalence and clinical correlates associated with EPS in a nonselected national multicenter sample of stabilized patients with schizophrenia. METHODS: Between 2010 and 2016, patients suffering from schizophrenia (DSM-IV-TR criteria) were recruited through the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) network and data were collected during a comprehensive 1-day-long standardized evaluation. The Simpson-Angus Scale and the Abnormal Involuntary Movement Scale were used to assess drug-induced parkinsonism (DIP) and tardive dyskinesia, respectively. RESULTS: The overall prevalence of DIP and tardive dyskinesia was 13.2% and 8.3%, respectively, in this community-dwelling sample of 674 patients. DIP was associated with negative symptoms (Positive and Negative Syndrome Scale [PANSS] subscore) (adjusted odds ratio [aOR] = 1.102, P < .001), first-generation antipsychotic prescription (aOR = 2.038, P = .047), and anticholinergic drug administration (aOR = 2.103, P = .017) independently of sex, age, disorganization (PANSS disorganized factor), and antipsychotic polytherapy. Tardive dyskinesia was associated with PANSS disorganized factor (aOR = 1.103, P = .049) independently of sex, age, negative symptoms, excitation, first-generation antipsychotic prescription, and benzodiazepine and anticholinergic drug administration. CONCLUSIONS: Our results indicate the high prevalence of EPS in a nonselected community-dwelling clinically stable sample of outpatients with schizophrenia. In the monitoring of antipsychotic treatment, EPS should be systematically evaluated, especially when negative symptoms and disorganization or cognitive alteration are present. Monotherapy with a second-generation antipsychotic should be preferentially initiated for patients with these side effects.

Screening for cognitive deficits with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale.

OBJECTIVE:: This study aimed to evaluate the validity of the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale (ECPDS) to discriminate for cognitive impairment in schizophrenia. DESIGN:: This multicentre cross-sectional study used a validation design with receiver operating characteristic (ROC) curve analysis. SETTINGS:: The study was undertaken in a French network of seven outward referral centres. SUBJECTS:: We recruited individuals with clinically stable schizophrenia diagnosed based on the Structured Clinical Interview for assessing Diagnostic and Statistical Manual of Mental Disorders (4th ed., rev.; DSM-IV-R) criteria. MAIN MEASURES:: The index test for cognitive impairment was ECPDS (independent variable), a 13-item scale completed by a relative of the participant. The reference standard was a standardized test battery that evaluated seven cognitive domains. Cognitive impairment was the dependent variable and was defined as an average z-score more than 1 SD below the normative mean in two or more cognitive domains. RESULTS:: Overall, 97 patients were included (67 with schizophrenia, 28 with schizoaffective disorder, and 2 with schizophreniform disorder). The mean age was 30.2 (SD 7.7) years, and there were 75 men (77.3%). There were 59 (60.8%) patients with cognitive impairment on the neuropsychological battery, and the mean ECPDS score was 27.3 (SD 7.3). The ROC curve analysis showed that the optimal ECPDS cut-off was 29.5. The area under the curve was 0.77, with 76.3% specificity and 71.1% sensitivity to discriminate against cognitive impairment. CONCLUSION:: The ECPDS is a valid triage tool for detecting cognitive impairment in schizophrenia, before using an extensive neuropsychological battery, and holds promise for use in everyday clinical practice.

Psychiatric disability as mediator of the neurocognition-functioning link in schizophrenia spectrum disorders: SEM analysis using the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale.

The functional outcome in schizophrenia spectrum disorders is affected by multiple factors such as cognitive performance and clinical symptoms. Psychiatric disability may be another important determinant of functional outcome. The purpose of this study was to test whether schizophrenia symptoms and psychiatric disability mediated the association between cognition and functioning. Between April 2013 and July 2017, we included 108 community-dwelling adults with stable schizophrenia spectrum disorder in a multicenter study. Psychiatric disability was assessed with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale by relatives of patients. ECPDS focused on the broad array of motivational, neurocognitive, sociocognitive, and metacognitive impairments that result in activity restrictions. We used a battery of tests to assess seven cognition domains (processing speed, attention/vigilance, working, verbal and visual memory, reasoning and problem solving, and executive functioning) and cross-sectional structural equation modeling (SEM) for the mediation analyses. We estimated the one-year temporal stability of ECPDS scores in 45 participants. The model provided showed good fit and explained 43.9% of the variance in functioning. The effect of neurocognition on functioning was fully mediated by symptoms (proportion mediated: 36.5%) and psychiatric disability (proportion mediated: 31.3%). The ECPDS score had acceptable one-year temporal stability. The ECPDS scale has satisfactory psychometric properties, and shows significant convergence with neurocognition and functioning, suggesting a role for this tool in the routine evaluation of cognitive remediation needs. Our model validates psychiatric disability as a crucial step from cognitive impairment to restricted participation in life situations.

Mediation Analyses of Insight, Quality of Life, Depression, and Suicidality: Results From the FACE-SZ Cohort.

OBJECTIVE: The relationship between greater insight and increased risk of suicide in patients with schizophrenia is debated. The purpose of this study was to assess whether quality of life (QoL) and depression mediated the association between insight and suicidality. METHODS: Between March 2010 and December 2015, 527 community-dwelling adults with stable schizophrenia according to DSM-IV criteria were included in a multicenter cross-sectional study, the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) Study. Structural equation modeling was used for mediation analyses among insight, QoL, depression, and suicidality, controlling for the global level of schizophrenic symptoms. RESULTS: The model provided a good fit for the data (χ²3 = 1.4, P = .708, Tucker-Lewis index = 1, comparative fit index = 1, root mean square error of approximation = 0, standardized root mean square residual = 0.008) and explained 27% of the variance in suicidality. Poorer QoL and greater severity of depression mediated 68.4% of the positive association between insight and suicidality (full mediation). Poorer QoL mediated 48% of the positive effect of insight on depression (partial mediation). The severity of depression mediated 91.2% of the negative relationship between QoL and suicidality (full mediation). CONCLUSIONS: Insight appears to be an indirect risk factor for suicide in patients with schizophrenia, with the link being mediated by poorer QoL and worse underlying depression, mainly by a sequential pathway but also by a less important parallel pathway.

Death by self-mutilation after oral cannabis consumption.

Major self-mutilation (amputation, castration, self-inflicted eye injuries) is frequently associated with psychiatric disorders and/or substance abuse. A 35-year-old man presented with behavioral disturbances of sudden onset after oral cannabis consumption and major self-mutilation (attempted amputation of the right arm, self-enucleation of both eyes and impalement) which resulted in death. During the enquiry, four fragments of a substance resembling cannabis resin were seized at the victim's home. Autopsy confirmed that death was related to hemorrhage following the mutilations. Toxicological findings showed cannabinoids in femoral blood (tetrahydrocannabinol (THC) 13.5 ng/mL, 11-hydroxy-tetrahydrocannabinol (11-OH-THC) 4.1 ng/mL, 11-nor-9-carboxy-THC (THC-COOH) 14.7 ng/mL, cannabidiol (CBD) 1.3 ng/mL, cannabinol (CBN) 0.7 ng/mL). Cannabinoid concentrations in hair (1.5 cm brown hair strand/1 segment) were consistent with concentrations measured in chronic users (THC 137 pg/mg, 11-OH-THC 1 pg/mg, CBD 9 pg/mg, CBN 94 pg/mg). Analysis of the fragments seized confirmed that this was cannabis resin with high levels of THC (31-35%). We discuss the implications of oral consumption of cannabis with a very high THC content.

Defining functioning levels in patients with schizophrenia: A combination of a novel clustering method and brain SPECT analysis.

This study aims to define functioning levels of patients with schizophrenia by using a method of interpretable clustering based on a specific functioning scale, the Functional Remission Of General Schizophrenia (FROGS) scale, and to test their validity regarding clinical and neuroimaging characterization. In this observational study, patients with schizophrenia have been classified using a hierarchical top-down method called clustering using unsupervised binary trees (CUBT). Socio-demographic, clinical, and neuroimaging SPECT perfusion data were compared between the different clusters to ensure their clinical relevance. A total of 242 patients were analyzed. A four-group functioning level structure has been identified: 54 are classified as "minimal", 81 as "low", 64 as "moderate", and 43 as "high". The clustering shows satisfactory statistical properties, including reproducibility and discriminancy. The 4 clusters consistently differentiate patients. "High" functioning level patients reported significantly the lowest scores on the PANSS and the CDSS, and the highest scores on the GAF, the MARS and S-QoL 18. Functioning levels were significantly associated with cerebral perfusion of two relevant areas: the left inferior parietal cortex and the anterior cingulate. Our study provides relevant functioning levels in schizophrenia, and may enhance the use of functioning scale.

Functional brain substrate of quality of life in patients with schizophrenia: A brain SPECT multidimensional analysis.

The aim of this study was to investigate the functional brain substrate of quality of life (QoL) in patients with schizophrenia. Participants comprised 130 right-handed patients with schizophrenia who underwent whole-brain single photon emission computed tomography (SPECT) with (99m)Tc-labeled ethylcysteinate dimer ((99m)Tc-ECD) for exploring correlations of regional cerebral blood flow (rCBF) with the eight dimensions score of the Schizophrenia Quality of Life questionnaire (S-QoL 18). A significant positive correlation was found between the global index of the S-QoL 18 and rCBF in the right superior temporal sulcus and between psychological well-being dimension and rCBF in Brodmann area (BA)6, BA8, BA9, and BA10 and between self-esteem dimension and rCBF in striatum and between family relationship dimension and rCBF in BA1, BA2, BA3, BA4, BA8, BA22, BA40, BA42 and BA44 and between relationship with friends dimension and rCBF in BA44 and between physical well-being dimension and rCBF in parahippocampal gyrus, and finally between autonomy dimension and rCBF in cuneus and precuneus. A significant negative correlation was found between resilience dimension and rCBF in precuneus and between sentimental life dimension and rCBF in BA10. Our findings provide neural correlates of QoL. Brain regions involved in cognitions, emotional information processing and social cognition underlie the different QoL dimensions.

A structural equation modelling approach to explore the determinants of quality of life in schizophrenia.

OBJECTIVE: This study aimed to analyse the relationships among psychotic symptoms, depression, neurocognition and functioning as determinants of quality of life (QoL) in patients with schizophrenia. METHODS: In this cross-sectional study, we evaluated QoL with the Schizophrenia Quality of Life 18-item scale (S-QoL 18), neurocognition with multiple tests exploring memory, attention and executive functions, the severity of psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS), depression with the Calgary Depression Scale for Schizophrenia (CDSS) and functioning using the Functional Remission Of General Schizophrenia (FROGS) scale. We used Structural Equation Modelling (SEM) to describe the relationships among the severity of psychotic symptoms, depression, neurocognition, functioning and QoL. RESULTS: Two hundred and seventy-one outpatients with schizophrenia participated in our study. SEM showed good fit with χ(2)/df=1.97, root mean square error of approximation=0.06, comparative fit index=0.93 and standardized root mean square residuals=0.05. This model revealed that depression was the most important feature associated with QoL, mainly for the self-esteem, autonomy and resilience dimensions (direct path coefficient=-0.46). The direct path between functioning and QoL was also significant (path coefficient=0.26). The severity of psychotic symptoms and neurocognitive impairment were weakly and indirectly associated with QoL via functioning (path coefficients=-0.18 and 0.04, respectively). CONCLUSIONS: This study contributes to a better understanding of the determinants of QoL in schizophrenia. Our findings should be considered in developing effective strategies for improving QoL among this population.

Neural substrate of quality of life in patients with schizophrenia: a magnetisation transfer imaging study.

The aim of this study was to investigate the neural substrate underlying quality of life (QoL) and to demonstrate the microstructural abnormalities associated with impaired QoL in a large sample of patients with schizophrenia, using magnetisation transfer imaging. A total of 81 right-handed men with a diagnosis of schizophrenia and 25 age- and sex-similar healthy controls were included and underwent a 3T MRI with magnetization transfer ratio (MTR) to detect microstructural abnormalities. Compared with healthy controls, patients with schizophrenia had grey matter (GM) decreased MTR values in the temporal lobe (BA21, BA37 and BA38), the bilateral insula, the occipital lobe (BA17, BA18 and BA19) and the cerebellum. Patients with impaired QoL had lower GM MTR values relative to patients with preserved QoL in the bilateral temporal pole (BA38), the bilateral insula, the secondary visual cortex (BA18), the vermis and the cerebellum. Significant correlations between MTR values and QoL scores (p < 0.005) were observed in the GM of patients in the right temporal pole (BA38), the bilateral insula, the vermis and the right cerebellum. Our study shows that QoL impairment in patients with schizophrenia is related to the microstructural changes in an extensive network, suggesting that QoL is a bio-psychosocial marker.

Investigation into alternative testing methodologies for characterization of influenza virus vaccine.

The objective of this study was to explore various testing methodologies suitable for characterizing sedimented or agglomerated material. To model this, bioCSL's split influenza virus vaccine, Fluvax® was utilized. The investigation was conducted on 5 dispensed lots of commercially manufactured vaccine, formulated for the 2013 Southern Hemisphere season. Vaccine syringes were initially inspected by visual tests; the material was then aseptically pooled for characterization assessment by microscopy and several agglomeration assays. All syringes passed bioCSL's description test where any fine or large sized particles of sediment observed in the vaccine were resuspended upon shaking; inverted light microscopy verified that the sediment morphology was consistent with influenza vaccine. Electron microscopic examination of pooled vaccine material demonstrated the presence of typical influenza structures including split virus, virosomes, whole virus particles and agglomerates. An optical density turbidity assay revealed relatively high protein recoveries in the vaccine supernatant post-centrifugation treatment, thus indicative of a well-dispersed vaccine formulation. This was corroborated by particle sizing analysis using dynamic light scattering which generated reproducible volume particle size distributions of a polydisperse nature. Ultraviolet-visible absorbance profiles further confirmed the presence of some agglomerated material. Data from all methods demonstrated consistent results between all batches of vaccine. Therefore, this investigation revealed the suitability and usefulness of the various methodologies in characterizing the appearance of agglomerated vaccine material. It is suggested that such methods may be applicable and beneficial for the development of a wider spectrum of heterogeneous and agglomerated formulations to provide safe, efficacious and superior quality biopharmaceutical products.

[Acute delirium in decompensated schizophrenia and bipolar disorder]. / Décompensation délirante aiguë des pathologies psychiatriques.

Acute delirium is common in decompensated schizophrenia and bipolar disor- der: more 50% in two years after the first episode of schizophrenia and 90% of patients with a diagnosis of bipolar disorder. Early signs precede in more 50% of cases the delirious exacerbation of 6 months. These non-specific signs are a change in the mood, an increase of anxiety, sleep and food disorders and suicidal ideation. After this prodromal phase, a persecutory delusion and hallucinations are often present in decompensated schizophrenia. In decompensated bipolar disorder, the delusional syndrome is congruent with the mood. The care should be the earliest possible. The treatment by antipsychotic or mood stabilizer must be increased or re-introduced and maintained during a long time in order to prevent a relapse. In parallel, a psychosocial care must be instituted.

Determinants of brain SPECT perfusion and connectivity in treatment-resistant depression.

This study aims to characterize and compare functional brain single photon emission tomography (SPECT) perfusion and connectivity in treatment-resistant depression (TRD) according to distinct demographic or clinical profiles (male vs. female; old vs. young; unipolar vs. bipolar) and to study their relationship to the severity and the duration of episode/illness. We retrospectively included 127 consecutive patients who met DSM-IV criteria for a nonpsychotic major TRD episode. All patients were studied using (99m)Tc-ethyl cysteinate dimer SPECT. Whole-brain, voxel-based, between-groups analyses were performed according to demographic and clinical data and in comparison to 37 healthy subjects. Voxel-wise interregional correlation was also performed to compare functional SPECT connectivity. Finally, relationships were searched for regarding severity and duration of episode/illness. The whole group of patients exhibited significant hypoperfusion within bilateral fronto-temporal, insular, and anterior cingulate cortices, as well as within the left caudate. Functional connectivity between left frontal and left cerebellar regions was higher in patients than in healthy subjects. Gender, age, and type of mood disorder did not influence these SPECT patterns. A significant relationship was found between brain SPECT perfusion and either duration or global severity of illness in particular frontal areas. Our data support the hypothesis of a shared SPECT pattern, whatever the profile of TRD, involving fronto-temporal regions and the cerebellum.

Neurophysiological correlates of metabolic syndrome and cognitive impairment in schizophrenia: a structural equation modeling approach.

OBJECTIVE: We aimed to investigate the brain functional substrate underlying relationships between metabolic syndrome (MetS) and cognitive impairment in schizophrenia. METHODS: In this cross-sectional study, we collected socio-demographic, clinical, anthropometric, blood, and cognition data and performed brain 99mTc-ECD-SPECT imaging of cerebral blood flow in patients with schizophrenia. Patients were grouped according to the absence or presence of MetS. Whole-brain perfusion SPECTs were compared at voxel level between these two groups, and voxel-wise interregional correlation was performed to compare functional connectivity (voxel level significance of p<0.005, uncorrected; p<0.05 for the cluster, uncorrected; using SPM8). A structural equation model (SEM) was applied to examine the relationships between brain perfusion, connectivity between brain areas, and cognition. RESULTS: Of the 55 patients, 17 had MetS. They performed significantly worse than patients without MetS on tests of executive functions (processing speed p=0.005 for TMT-A; and reactive flexibility p=0.014 for TMT-B), attention (D2 attention task p=0.007), and memory (California Verbal Learning Test p=0.039). In comparison to patients without MetS, those with MetS exhibited significant hypoperfusion within the left orbital prefrontal cortex and greater functional connectivity from this left frontal cluster within the left insula and middle/superior frontal gyrus. SEM confirmed the effect on executive functions of brain hypoperfusion and of increased connectivity, suggesting possible compensatory networks in patients with MetS. CONCLUSION: Our study identifies the brain functional impact of MetS on cognition, with orbital prefrontal impairment and possible compensatory networks.

Validation of a functional remission threshold for the Functional Remission of General Schizophrenia (FROGS) scale.

OBJECTIVE: The aim of this study was to develop a functional remission threshold for the Functional Remission Of General Schizophrenia (FROGS) scale, and test its validity regarding clinical and quality of life outcomes. DESIGN: Cross-sectional study. INCLUSION CRITERIA: Schizophrenia according to DSM-IV-TR criteria. DATA COLLECTION: Functioning was assessed using the FROGS and the Global Assessment of Functioning (GAF) scales; psychotic symptoms using the Positive and Negative Syndrome Scale; memory, attention, and executive functions were assessed using the California Verbal Learning Test, the D2 attention task, the Stroop color-word test, the verbal fluency test, the Trail Making Test A and B and the Wechsler Adult Intelligence Scale; and quality of life using the schizophrenia quality of life (S-QoL 18) scale. ANALYSIS: A logistic regression analysis including the different dimensions of the FROGS was used to create a composite score to classify patients into remitted and non-remitted according a gold standard (cut-off: GAF>= 61). Receiver operating characteristics analyses were then performed to determine the area under the curve (AUC). RESULTS: Of 137 patients enrolled, 26 were functionally remitted and 111 were not remitted according to GAF score. The AUC for the combination of the FROGS's dimensions to detect functional remission was 0.903 (p<0.001). Sensitivity and specificity for the combination of the FROGS dimensions using the Youden index were 88.5 [69.8; 97.6] and 81.1 [72.5; 87.9], respectively. Validity of this combination was satisfactory. Patients in functional remission had a lower severity of the disease, especially for PANSS negative (p<0.001) and general psychopathology (p<0.001) symptoms. Only two cognitive functions (i.e. fluency and episodic memory) were improved in remitted patients. Higher quality of life levels were globally associated with better functioning. CONCLUSIONS: These findings provide for first accurate FROGS thresholds to detect functional remission in schizophrenia.

Schizophrenia with preserved insight is associated with increased perfusion of the precuneus.

BACKGROUND: Preserved insight into illness has been suggested to be predictive of outcome in patients with schizophrenia. We aimed to investigate the functional substrate underlying preserved insight in these patients. METHODS: We recruited patients with paranoid schizophrenia and healthy controls matched for age and sex. Patients were grouped according to preserved or impaired insight into illness using the Scale to assess Unawareness of Mental Disorder (SUMD). Whole-brain technetium-99m ethyl cysteinate dimer single photon emission computed tomography regional cerebral blood flow was compared at the voxel level between the 2 groups using a statistical parametric map (voxel-level significance of p < 0.001, uncorrected; cluster level significance of p < 0.05, uncorrected). RESULTS: We enrolled 31 right-handed patients with schizophrenia and 18 controls in our study. Twenty-one (67.7%) patients had preserved insight. The 2 groups did not differ significantly in demographic and clinical characteristics or in treatment. Compared with controls, the whole group of patients showed bilateral frontotemporal hypoperfusions, with no statistical difference between patients with preserved or impaired insight for these areas. Patients with preserved insight showed significantly increased perfusion of the bilateral precuneus relative to those with impaired insight. LIMITATIONS: Patients with subtypes other than paranoid schizophrenia have to be investigated to assess whether involvement of the precuneus in patients with preserved insight can be identified across the full spectrum of subtypes and symptoms of schizophrenia. Moreover, our study concerned only the central dimension (awareness of mental disorder) of 1 scale (SUMD); other dimensions of insight could be studied. CONCLUSION: Our results show that schizophrenia with preserved insight is associated with greater perfusion of the precuneus, a brain area known to be involved in self- consciousness, suggesting a compensatory mechanism of fronto-temporal impairment.

Rapid generation of pandemic influenza virus vaccine candidate strains using synthetic DNA.

BACKGROUND: Vaccination is considered the most effective means of reducing influenza burden. The emergence of H5N1 and pandemic spread of novel H1N1/2009 viruses reinforces the need to have strategies in place to rapidly develop seed viruses for vaccine manufacture. METHODS: Candidate pandemic vaccine strains consisting of the circulating strain haemagglutinin (HA) and neuraminidase (NA) in an A/PR/8/34 backbone were generated using alternative synthetic DNA approaches, including site-directed mutagenesis of DNA encoding related virus strains, and rapid generation of virus using synthetic DNA cloned into plasmid vectors. RESULTS: Firstly, synthetic A/Bar Headed Goose/Qinghai/1A/2005 (H5N1) virus was generated from an A/Vietnam/1194/2004 template using site-directed mutagenesis. Secondly, A/Whooper Swan/Mongolia/244/2005 (H5N1) and A/California/04/09 (H1N1) viruses were generated using synthetic DNA encoding the viral HA and NA genes. Replication and antigenicity of the synthetic viruses were comparable to that of the corresponding non-synthetic viruses. CONCLUSIONS: In the event of an influenza pandemic, the use of these approaches may significantly reduce the time required to generate and distribute the vaccine seed virus and vaccine manufacture. These approaches also offer the advantage of not needing to handle wild-type virus, potentially diminishing biocontainment requirements.

The development of vaccine viruses against pandemic A(H1N1) influenza.

Wild type human influenza viruses do not usually grow well in embryonated hens' eggs, the substrate of choice for the production of inactivated influenza vaccine, and vaccine viruses need to be developed specifically for this purpose. In the event of a pandemic of influenza, vaccine viruses need to be created with utmost speed. At the onset of the current A(H1N1) pandemic in April 2009, a network of laboratories began a race against time to develop suitable candidate vaccine viruses. Two approaches were followed, the classical reassortment approach and the more recent reverse genetics approach. This report describes the development and the characteristics of current pandemic H1N1 candidate vaccine viruses.