Cannabis Use and Symptomatic Relapse in First Episode Schizophrenia: Trigger or Consequence? Data From the OPTIMISE Study.

BACKGROUND AND HYPOTHESIS: This analysis examined the relationship between cannabis use, compliance with antipsychotics and risk for relapse in patients in remission following a first episode of schizophrenia, schizophreniform, or schizoaffective disorder. STUDY DESIGN: Analyses were performed on data from a large European study on first episode of schizophrenia, schizophreniform, or schizoaffective disorder (OPTiMiSE). After 10 weeks of antipsychotic treatment, 282/446 patients (63%) met criteria for symptomatic remission; of whom 134/282 (47.5%) then completed a 1-year follow-up. Cross-lagged models and mediation models investigated the temporal relationships between cannabis use, compliance with antipsychotics, social functioning, and symptomatic worsening/relapse. STUDY RESULTS: Compared to nonusers, cannabis use increased risk for relapse, adjusted hazard ratio (HR) = 3.03 (SE = 0.32), P < .001, even in patients who were compliant with antipsychotic medication, adjusted HR = 2.89, (SE = 0.32), P < .001. Cannabis use preceded symptomatic worsening and was followed by worsening of Positive and Negative Syndrome Scale total score at the 1-year end-point (standardized ß = 0.62, SE = 0.19, P = .001) and by worsening of social functioning (coef = -0.66, P ≤ .001). CONCLUSIONS: In patients in remission from their first episode of schizophrenia, schizophreniform, or schizoaffective disorder, cannabis use increases the rate of relapse in both compliant and noncompliant individuals. Importantly, the temporal relationship between cannabis and relapse was that cannabis use preceded later relapse, noncompliance, and decrease in social functioning, and not that patients began to relapse, then used cannabis. Further research with a precision psychiatry approach might identify those patients in particular danger of relapse when using cannabis.

Scalability of the Positive and Negative Syndrome Scale in first-episode schizophrenia assessed by Rasch models.

OBJECTIVE: Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30-item PANSS total score as well as the scalability of a shorter version (PANSS-6) of the scale. METHODS: A composite data set of 1073 patients with first-episode schizophrenia or schizophrenia spectrum disorder was subjected to Rasch analysis of PANSS data from baseline and 4-6 weeks follow-up. RESULTS: The central tests of fit of the Rasch model failed to satisfy the statistical requirements behind item homogeneity for the PANSS-30 as well as the PANSS-6 total score. For the PANSS-30, Differential Item Functioning was pronounced both for the 7-point Likert scale rating categories and when dichotomizing the rating categories. Subsequently, the Rasch structure analysis in the context of dichotomized items was used to isolate and estimate a systematic error because of item inhomogeneity, as well as a random error. The size of the combined sources of error for the PANSS-30 total score approximated 20% which is often regarded as clinical cut-off between response versus no-response. CONCLUSION: The results demonstrate the operational consequences of a lack of statistical fit of the Rasch model and suggest that the calculated measure of uncertainty needs to be considered when using the PANSS-30 total score.

Executive Dysfunctions Predict Self-Restricted Driving Habits in Elderly People with or without Alzheimer's Dementia.

Introduction The purpose of this study was to elucidate the impact of specific cognitive functions on self-restricted driving habits in healthy elderly drivers and patients suffering from mild cognitive impairment (MCI) and Alzheimer's dementia (AD). Method Our study population included 35 cognitively healthy controls, 10 MCI patients, and 16 patients with AD. All participants completed a neuropsychological examination and a self-reported questionnaire assessing driving habits and patterns. Results In challenging driving conditions, patients with MCI or AD showed significantly more driving self-restriction than healthy subjects (effect size d=1.06, p=0.007). Ordinal regression analysis across the entire group revealed that deficits in executive functions and reaction had a higher impact on driving restriction (p=0.002) than deficits in memory functions (p=0.570). Additionally, our data showed that 40% of patients with mild to moderate AD still drive in challenging conditions. Discussion Our results illustrate that elderly individuals use self-imposed driving restrictions as compensatory strategies. These restrictions increase with cognitive decline mainly in the field of executive functions, but they do not change once patients convert from MCI to AD.

Bitopertin in Negative Symptoms of Schizophrenia-Results From the Phase III FlashLyte and DayLyte Studies.

BACKGROUND: There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. METHODS: Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24. RESULTS: The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated. CONCLUSIONS: These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia.

Multisite prediction of 4-week and 52-week treatment outcomes in patients with first-episode psychosis: a machine learning approach.

BACKGROUND: At present, no tools exist to estimate objectively the risk of poor treatment outcomes in patients with first-episode psychosis. Such tools could improve treatment by informing clinical decision-making before the commencement of treatment. We tested whether such a tool could be successfully built and validated using routinely available, patient-reportable information. METHODS: By applying machine learning to data from 334 patients in the European First Episode Schizophrenia Trial (EUFEST; International Clinical Trials Registry Platform number, ISRCTN68736636), we developed a tool to predict poor versus good treatment outcome (Global Assessment of Functioning [GAF] score ≥65 vs GAF <65, respectively) after 4 weeks and 52 weeks of treatment. To enable the unbiased estimation of the predictive system's generalisability to new patients, we used repeated nested cross-validation to prevent information leaking between patients used for training and validating the models. In pursuit of everyday clinical applicability, we retrained the 4-week outcome predictor with only the top ten predictors of the pooled prediction system and then tested this tool in 108 independent patients with 4-week outcome labels. Discontinuation and readmission to hospital events in patients with predicted poor versus good outcomes were assessed with Kaplan-Meier log-rank analyses, whereas generalised linear mixed-effects models were used to investigate the GAF-based predictions against several clinically meaningful outcome indicators, including treatment adherence, symptom remission, and quality of life. FINDINGS: The generalisability of our outcome predictions were estimated with cross-validation (test-fold balanced accuracy [BAC] of 75·0% for 4-week outcomes and 73·8% for and 52-week outcomes), and leave-site-out validation across 44 European sites (BAC of 72·1% for 4-week outcomes and 71·1% for 52-week outcomes). We identified a smaller group of ten predictors still providing a BAC of 71·7% in 108 patients never used for model discovery. Unemployment, poor education, functional deficits, and unmet psychosocial needs predicted both endpoints, whereas previous depressive episodes, male sex, and suicidality additionally predicted poor 1-year outcomes. 52-week predictions identified patients at risk for symptom persistence, non-adherence to treatment, readmission to hospital and poor quality of life. Specifically among these patients, amisulpride and olanzapine showed superior efficacy versus haloperidol, quetiapine, and ziprasidone. INTERPRETATION: Our results suggest that prognostic models operating on brief, patient-reportable pre-treatment data might provide useful insight into individualised outcome trajectories, optimising treatment selection, and targeted clinical trial designs. To embed these tools into real-world care, replication is needed in external first-episode samples with overlapping variables, which are not available in the field at present. FUNDING: The European Group for Research in Schizophrenia.

Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study.

BACKGROUND: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18-70 years) with schizophrenia, previously stabilized on PP1M. METHODS: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. RESULTS: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. CONCLUSION: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.

Affective prosody perception in symptomatically remitted patients with schizophrenia and bipolar disorder.

Affect perception has frequently been shown to be impaired in patients suffering from schizophrenia or bipolar disorder (BD), but it remains unclear whether these impairments exist during symptomatic remission and whether the two disorders differ from each other in this regard. Most previous studies have investigated facial affect recognition, but not the ability to decode mental states from emotional tone of voice, i.e. affective prosody perception (APP). Accordingly, the present study directly compared APP in symptomatically remitted patients with schizophrenia or BD and healthy control subjects and investigated its relationship with residual symptomatology in patients. Patients with schizophrenia and BD showed comparable APP impairments despite being symptomatically remitted. In comparison to healthy control subjects, overall APP deficits were found in BD but not in schizophrenia patients. Both patient groups were particularly impaired in the identification of anger and confounded it with neutral prosody. In addition, schizophrenia patients frequently confused sadness with happiness, anger, or fright. There was an inverse association between the degree of residual positive symptoms and the ability to correctly recognize happiness in schizophrenia patients. Overall, these data indicate that impairments in APP represent an enduring deficit and a trait marker of both schizophrenia and BD and that the level of impairment is comparable between disorders.

How antipsychotics impact the different dimensions of Schizophrenia: a test of competing hypotheses.

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness. We validated the generalizability of the model in further trials involving antipsychotics in chronic [1460 patients] and first-episode patients [1053 patients]. Across different populations, different trials and different antipsychotics - the best-fitting model suggests that symptom response in schizophrenia is underpinned by a single general effect with secondary and minor lower-order effects on specific symptom domains. This single-factor model explained nearly 80% of the variance, was superior to the assumption of unique efficacy for specific domains; and replicated across antipsychotics and illness stages. Despite theoretical and pharmacological claims the differential efficacy of antipsychotics on the various dimensions of schizophrenia is not supported in the prevailing data. The implication of this finding for the measurement of treatment response and our understanding of the neurobiology of antipsychotic action, for clinical practice and for future drug development are discussed.

Is the ongoing use of placebo in relapse-prevention clinical trials in schizophrenia justified?

BACKGROUND: Placebo-controlled randomised controlled trials (RCTs) continue to be required or recommended by regulatory authorities for the licensing of new drugs for schizophrenia, despite ongoing concerns regarding the risks to trial participants. METHODS: In this article we consider the scientific and ethical pros and cons associated with use of placebo in RCTs in schizophrenia, systematically review the published relapse-prevention placebo-controlled RCTs with second generation antipsychotics (SGAs) in schizophrenia, and examine the risks associated with these trials. RESULTS: We identified 12 studies involving 2842 participants of which 968 received placebo. Relapse rates were 56% for placebo and 17.4% for active treatment groups. There is a lack of well-designed longitudinal studies investigating the psychosocial and biological consequences of exposure to placebo, to treatment discontinuation and to relapse in schizophrenia. CONCLUSION: In the absence of such studies it is risky to assume that patients are not at risk of significant distress and long-term harm, and therefore it is difficult to justify the ongoing use of placebo in relapse-prevention RCTs in schizophrenia.

Aripiprazole treatment for patients with schizophrenia: from acute treatment to maintenance treatment.

The most current treatment guidelines for schizophrenia recommend more than 1 year of maintenance therapy after the first psychotic episode, and more than 5 years of maintenance therapy after multiple psychotic episodes. Approximately two-thirds of such patients are known to relapse within 1 year and almost 90% of such patients may recur within 2 years. To maintain adequate consistent treatment, balancing the efficacy and safety/tolerability should be one of the most important clinical issues. In this respect, aripiprazole appears to be a good treatment option owing to its comparable efficacy, favorable safety and tolerability profile, including low incidence of parkinsonian symptoms, lack of prolactin elevation, decreased adrenergic and anticholinergic side effects, less weight gain and low incidence of metabolic syndrome. Hence this article aims to summarize the currently available clinical trial data of aripiprazole published from a number of large-scale randomized controlled studies, including a newer formulation of intramuscular injection as well as a once-monthly intramuscular depot formulation, to update knowledge of treatment options in patients with schizophrenia.

Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study.

BACKGROUND: Profile and correlates of cognitive deficits in first episode (FE) schizophrenia patients are still debated. The present study is aimed to clarify in a large sample of FE patients the extent of impairment in key cognitive domains and its relationships with demographic and clinical variables. METHOD: The European First Episode Schizophrenia Trial collected demographic, clinical and neurocognitive baseline data in 498 FE patients with minimal or no prior exposure to antipsychotics. Two-hundred-twenty healthy subjects (HS) were also evaluated. Neurocognitive assessment included the Rey Auditory Verbal Learning Test; Trail Making A and B, Purdue Pegboard and Digit-Symbol Coding. RESULTS: Patients performed worse than HS on all tests (effect sizes from -0.88 to -1.73). Correlations with psychopathological dimensions were weak and involved reality distortion and disorganization. The duration of untreated psychosis (DUP) was not associated with cognitive impairment. Subjects living alone had a better neurocognitive performance, while the occupation status did not reveal any association with cognition. CONCLUSIONS: A moderate/severe impairment of processing speed, motor dexterity, verbal memory and cognitive flexibility was found in the largest sample of FE patients analyzed so far. The impairment was largely independent from psychopathology and not associated with DUP.

Akathisia: an updated review focusing on second-generation antipsychotics.

OBJECTIVE: To provide a brief description of the pathophysiology of akathisia, the challenges of diagnosing and treating this condition, and potential associated clinical issues. Also, to provide a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs). DATA SOURCES: English-language literature with no date restrictions cited in PubMed was searched for the keywords akathisia, placebo, neuroleptic, or haloperidol, and the generic names of SGAs (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole). STUDY SELECTION: Limits were set to search clinical trials, meta-analyses, or randomized controlled trials reviewing data from adult schizophrenia or bipolar disorder clinical trials. Studies including SGA comparisons with placebo and with FGAs, and also between SGAs themselves, were selected. Studies that specifically assessed akathisia (either subjectively or objectively or both) were included. Studies reporting generalized results pertaining to extrapyramidal symptoms (EPS) were excluded. DATA EXTRACTION: The incidence of akathisia, EPS rating scores, and required medications for the management of movement disorders were reviewed. DATA SYNTHESIS: Seventy-seven trials were included in the comparative review. Akathisia was observed with the use of all the SGAs. The akathisia incidence reported in bipolar disorder trials was generally higher compared with schizophrenia trials. The incidence reported for FGAs was consistently higher than that reported for SGAs, regardless of the patient population studied. CONCLUSION: Akathisia remains a concern with the use of SGAs. More accurate and standardized evaluations are required for a better understanding of the nature and incidence of akathisia.

Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST).

OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Compliance in schizophrenia: psychopathology, side effects, and patients' attitudes toward the illness and medication.

OBJECTIVE: In a cross-sectional study, we investigated the influence of several factors on compliance in schizophrenia outpatients, including patients' attitudes toward the illness and medication, specifically antipsychotic medication; adverse effects; and attitudes of caregivers and relatives toward the illness and medication. METHOD: Patients suffering from schizophrenia (ICD-10 diagnosis) of at least 1-year's duration whose discharge from an inpatient ward was at least 6 weeks prior to inclusion in the study were investigated. Study instruments included a semi-structured compliance interview, the Positive and Negative Syndrome Scale, the Udvalg for Klinske Undersogelser Side Effect Rating Scale, the St. Hans Rating Scale, and the Hillside Akathisia Scale. Data were collected from May 1998 to December 2001. RESULTS: 52.5% (N = 32) of the 61 investigated patients were fully compliant, 39.3% (N = 24) were partially compliant, and only 8.2% (N = 5) were noncompliant. We found positive correlations between compliance and the patients' feelings of a positive effect of the drug on the illness, between compliance and negative symptoms, and between compliance and antipsychotic-induced psychological side effects. CONCLUSION: Our findings reemphasize the importance of taking subjective attitudes and concerns of patients with respect to their illness and medication seriously. Therefore, it is indispensable to include patients and, if possible, their relatives in the treatment decision process to enhance medication compliance in schizophrenia patients.

Differential effects of phencyclidine application on secretogranin II expression in organotypic slices of rat prefrontal cortex.

Phencyclidine (PCP) is a non-competitive NMDA glutamate receptor antagonist that induces psychotomimetic effects in humans and experimental animals. Chronic PCP exposure elicits signs of persistently altered frontal brain activity and related behaviors which are also seen in patients with schizophrenia. Secretogranin II (sg II) belongs to the chromogranin family of proteins that exist in large dense core vesicles in nervous tissue. In the brain, 90% of sg II is processed to the small peptide secretoneurin. We previously detected differential effects of single-dose and subchronic PCP administration on sg II expression in the rat prefrontal cortex (PFC). In the present study, we applied PCP to organotypic PFC slices. PCP application for 28 h induced decreased tissue and culture medium secretoneurin content. In contrast, incubation with the adenylate cyclase activator forskolin caused significantly increased secretoneurin levels after 8 h. PCP for 4 h followed by 24 h without PCP resulted in increased culture medium secretoneurin content but no change in tissue levels. sg II mRNA expression was decreased after 28 h PCP application in cortical neurons. Immunohistochemical and TUNEL staining profiles indicated that the alterations were not due to neurodegeneration. PCP for 5 days changed neither the secretoneurin tissue or culture medium levels, nor the sg II mRNA expression. These results demonstrate that PCP modulates sg II expression in PFC tissue in the absence of afferent inputs and that the nature of these changes is dependent upon the duration of exposure to and/or withdrawal from PCP.