Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST).

BACKGROUND: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. METHODS: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. FINDINGS: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. INTERPRETATION: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. FUNDING: Lundbeck and Otsuka.

Over-Reporting of Somatic and Psychiatric PTSD Symptoms Among People Who Experienced Motor Vehicle Accidents and Did Not Seek Psychiatric Help in a Primary Care Setting.

Background: Over-reporting of posttraumatic stress disorder (PTSD) symptoms has been observed in some cases, following a motor vehicle accident (MVA). It has been suggested, however, that these are cases of underdiagnoses in primary care settings. The current study focused on people with PTSD in primary care settings who experienced an MVA and do not seek psychiatric help. Methods: In the over 3000 patient registry of a primary care clinic, 174 people who experienced an MVA (PE-MVA) were identified. The final sample included 45 PE-MVA, who were administered the Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS-2), and completed the Injury Severity Scale (ISS) and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) content scales. Results: PE-MVA with PTSD reported more psychopathology on both MMPI-2 and CAPS-2 than those without PTSD. Severity of injury, measured by the ISS, did not differ significantly between the two PE-MVA groups. The significant differences between the PE-MVA with PTSD and those without PTSD disappeared after adjusting for the covariates of bias scales [Infrequency (F) and Fake Bad (FBS)] in MMPI-2, but not in CAPS-2. Conclusion: The results suggest that in primary care settings, PE-MVA with PTSD who do not seek psychiatric help, over-report psychiatric and somatic symptoms. In a personal injury setting the F scale of the MMPI-2 showed less sensitivity to exaggerated somatic symptoms than the FBS scale. Bias scales of PE-MVA with PTSD are major contributors to the elevation of the MMPI-2 scores but not the CAPS-2 score.

The Influence of Substance Abuse on Inhibition Capacities and Risky Decision in a Group of Outpatient Schizophrenia Patients.

OBJECTIVE: Substance abuse is common among patients with schizophrenia, is related to worse course and outcome of illness. Unfortunately, little is known about how substance abuse affects the cognitive function of schizophrenia patients, whose cognitive function is often already comprised. Neurocognitive functioning includes inhibition control and decision-making, and both schizophrenia and substance use disorder are related to impairments of inhibition control. However, the influence of substance abuse on inhibition capacities among schizophrenia patients is unclear. Methods: This study measured the influence of substance use disorder on inhibition capacities and risky decision-making in a group of 39 schizophrenia patients that were evaluated using a socio-demographic questionnaire and clinical assessment using the Positive and Negative Syndromes Scale for Schizophrenia. To assess inhibition control we utilized the Matching Familiar Figure Test (MFFT) and the Stroop task, and to evaluate decision-making we used the Iowa Gambling Task (IGT) and self-report questionnaire, the Barratt Impulsiveness Scale. Results: Univariate analysis found significant differences between the groups with regard to criminal history (χ2 = 5.97, p=.015), smoking status (χ2 = 12.30, p<.001), and total BIS score (t= -2.69, df = 37, p=.01). Our model did not find a significant effect of substance abuse on the first response time and number of errors on the MFFT or in the total interference index of Stroop performance and net score on risky decision-making in the IGT. The two groups did not differ significantly either in first response time or in number of errors on the MFFT (F = 0.54, p=.47, d = 0.24, 95% CI [-0.4, 0.88]; F = 0.28, p=.60, d = 0.61, 95% CI [0, 1.26], respectively), nor did they differ in the total interference index of the Stroop task (F(1)=0.49, p=.49, d = 0.25, 95% CI [-0.38, 0.88]). Conclusion: The analyses did not detect any statistically significant effect of substance abuse on inhibition control or risky decision-making processes in outpatients diagnosed with schizophrenia, despite increased impulsivity, criminal history and smoking status. These results neither support nor disprove previous findings.

Social affective context reveals altered network dynamics in schizophrenia patients.

Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social-affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks' NCI dynamic during the social-affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social-affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another's' distress may underlie social-affective deficits in schizophrenia.

Never resting region--mPFC in schizophrenia.

Reduced functional connectivity (FC) in schizophrenia has been demonstrated either in task related or 'default network' areas, but not between these networks, which interact meaningfully. We examined the role of FC between the inferior frontal gyrus (IFG) and medial prefrontal cortex (mPFC) in determining language-lateralization during a language task, and its association with structural integrity of the corpus-callosum. Only schizophrenia patients presented increased mPFC-IFG FC during task, which additionally corresponded to decreased white-matter organization of the corpus-callosum. These findings suggest that inability to suppress irrelevant internally-generated information while processing external stimuli might be the basis of functional psychopathology in schizophrenia.

Global functional connectivity deficits in schizophrenia depend on behavioral state.

Schizophrenia is a devastating psychiatric illness characterized by deterioration of cognitive and emotional processing. It has been hypothesized that aberrant cortical connectivity is implicated in the disease (Friston, 1998), yet previous studies of functional connectivity (FC) in schizophrenia have shown mixed results (Garrity et al., 2007; Jafri et al., 2008; Lynall et al., 2010). We measured FC using fMRI in human schizophrenia patients and healthy controls during two different tasks and a rest condition, and constructed a voxel-based global FC index. We found a striking FC decrease in patients compared with controls. In the task conditions, relatively weaker FC was specific to regions of cortex not active during the task. In the rest condition, the FC difference between patients and controls was larger and allowed a case-by-case separation between individuals of the two groups. The results suggest that the relative reduction of FC in schizophrenia is dependent on the state of cortical activity, with voxels not activated by the task showing higher levels of FC deficiency. This novel finding may shed light on previous reports of FC in schizophrenia. Whether this neural characteristic is related to the development of the disorder remains to be established.

Demographic and clinical characteristics of motor vehicle accident victims in the community general health outpatient clinic: a comparison of PTSD and non-PTSD subjects.

Motor vehicle accidents (MVAs) are the leading cause of posttraumatic stress disorder (PTSD) in the general population, often with enduring symptomatology. This study details epidemiological and clinical features that characterize PTSD among MVA victims living in a nonhospitalized community setting long after the MVA event, and includes exploration of premorbid and peritraumatic factors. MVA victims (n=60; 23 males, 37 females) identified from the registry of a community general health outpatient clinic during a 7-year period were administered an extensive structured battery of epidemiological, diagnostic and clinical ratings. Results indicated that 30 subjects (50%; 12 males, 18 females) had MVA-related PTSD (MVAR-PTSD). Among those with PTSD, 16 individuals exhibited PTSD in partial remission, and six, in full remission. There were no significant demographic or occupational function differences between PTSD and non-PTSD groups. The most common comorbid conditions with MVAR-PTSD were social phobia (20%), generalized anxiety disorder (7.8%) and obsessive-compulsive disorder (0.5%). Previous MVA's were not predictive of PTSD. Subjects with MVAR-PTSD scored worse on the Clinician-Administered Posttraumatic Stress Disorder Scale, Part 2 (CAPS-2), Impact of Event Scale, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Impulsivity Scale, and Toronto Alexithymia Rating Scale. Study observations indicate a relatively high rate of PTSD following an MVA in a community-based sample. The relatively high rate of partially remitted MVAR-PTSD (N=16) underscores the importance of subsyndromal forms of illness. Alexithymia may be an adaptive method of coping with event stress. The development of PTSD appears not to be associated with the severity of MVA-related physical injury.

Comparison between risperidone, olanzapine, and clozapine in the management of chronic schizophrenia: a naturalistic prospective 12-week observational study.

Risperidone, olanzapine, and clozapine are three atypical antipsychotic medications commonly used in the management of chronic schizophrenia. While they offer advantages with regard to clinical efficacy and side-effect profile, few studies have compared them in a naturalistic prospective observational manner. This study therefore investigated their comparative efficacy over 12 weeks including illness characteristics and adverse effects. One hundred thirty-one patients (76 M, 55 F) with DSMI-V schizophrenia or schizoaffective disorder were treated with risperidone (n = 38), olanzapine (n = 38), or clozapine (n = 55). All patients showed a significant decrease of Positive and Negative Syndrome Scale (PANSS)-positive scores. Decreases in tardive dyskinesia and impulsivity scores were noted with clozapine and olanzapine, respectively. No differences between the medications were noted on depression, anxiety, EPS, or overt aggression scores. Olanzapine and clozapine appeared to be more effective in females. Males showed a decreased sexual performance irrespective of the medication and those treated with risperidone and clozapine showed greater proportional reduction of overt aggression. Clozapine-treated patients showed significant increased weight, increased glucose levels, and lowered sexual performance. Risperidone patients tended to exhibit reduced cholesterol levels. Higher creatine kinase (CK) levels were noted in risperidone-treated patients. While cautious given the nature of the study design, results suggest differences in the response to various atypical antipsychotic medications regarding efficacy and side-effect susceptibility.