Raloxifene augmentation in men and women with a schizophrenia spectrum disorder:A study protocol

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered

Multivariable prediction of functional outcome after first-episode psychosis:a crossover validation approach in EUFEST and PSYSCAN

Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current &lt; 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended.</p

PsyCog:A computerised mini battery for assessing cognition in psychosis

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) ( N = 135), Clinical High Risk (CHR) ( N = 233), and First Episode Psychosis (FEP) ( N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design. </p

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort

[Background] We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN).[Method] Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study.[Results] The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period.[Conclusions] This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.PSYSCAN was supported as part of the European Funding 7th Framework Programme (grant number 603196).Peer reviewe

Supplements to: A naturalistic cohort study of first-episode schizophrenia spectrum disorder: a description of the early phase of illness in the PSYSCAN cohort

Suppl. Figure 1. Percentage of FES patients in symptomatic remission throughout the study.Suppl. Figure 2. Percentage of FES patients in functional remission throughout the study.Suppl. Figure 3. Clustered boxplot displaying the mean depression scores per time point (measured using the Hamilton Depression Rating Scale) in the subgroup meeting criteria for a depressive episode at baseline (assessed through the SCID-I) versus the subgroup without a depressive episode at baseline.Suppl. Table 1. Baseline demographics and clinical characteristics of study completers and drop-outs.Suppl. Table 2. Number of patients in symptomatic and functional remission throughout the period of follow-up.Suppl. Table 3. Generalized linear mixed models: pairwise contrasts for symptomatic and functional remission.Suppl. Table 4. Linear mixed models: estimated marginal means for PANSS, GAF, SOFAS, CGI, GF-S, GF-R and HAM-D.Suppl. Table 5. Linear mixed models: estimates of fixed effect time on PANSS, GAF, SOFAS, CGI, GF-S, GF-R and HAM-D.Suppl. Table 6. Number of patients admitted to the hospital since the previous visit due to psychotic symptoms and due to psychiatric reasons in general.Suppl. Table 7. Substances used at least once in the past three months (WHO-ASSIST).Suppl. Table 8. Number of patients reporting daily or almost daily substance use in the past three months, separated per time point and substance category (WHO-ASSIST).Suppl. Table 9. Number of patients reporting daily or almost daily substance use in the past three months, separated for the group of symptomatic remitters and non-remitters at month 12.Suppl. Table 10. Baseline demographics and clinical characteristics of symptomatic remitters and non-remitters at month 12.Suppl. Table 11. Summary of sociodemographics and baseline clinical characteristics of FES participants, separated per country.Suppl. Table 12. Number of FES patients in symptomatic remission throughout the period of follow-up, separated per country.Suppl. Table 13. Number of FES patients in functional remission throughout the period of follow-up, separated per country.Suppl. Table 14. Number of FES patients admitted to the hospital for psychiatric reasons throughout the period of follow-up, separated per country.Suppl. Table 15. Number of FES patients admitted to the hospital for psychosis throughout the period of follow-up, separated per country.Suppl. Table 16. Number of FES patients using antipsychotic medication throughout the period of follow-up, separated per country.Suppl. Table 17. Overview of subjects not meeting eligibility criteria.Suppl. Table 18. Number of patients in symptomatic and functional remission throughout the period of follow-up when using alternative definitions.Suppl. Table 19. Generalized linear mixed models: pairwise contrasts for symptomatic and functional remission when using alternative definitions.Peer reviewe

Forgetting the new locations of one’s keys: spatial-memory interference in Korsakoff’s amnesia

The present study focused on interference in a group of patients with amnesia due to Korsakoff’s syndrome (KS) within the domain of spatial memory. An object–location memory task was used in which participants first learned an array of objects on a computer screen, followed by a reconstruction of the object positions. Next a trial was given in which the same objects were presented only now in different locations. Participants had to place the objects a second time but at the new locations. This was repeated for seven pairs of baseline/interference trials. Both Korsakoff patients and matched controls did worse on the interference trials than on the baseline trials, indicating that it is difficult to relearn new spatial locations for objects that previously were remembered in other locations. When computing relative interference effects (that is the percentage change from baseline in the interference trials), Korsakoff patients were less affected than controls. It is discussed in how far interference depends on the strength of the original memories, which are markedly lower in KS patients

Treating auditory hallucinations with transcranial direct current stimulation in a double-blind, randomized trial

Objective: Transcranial direct current stimulation (tDCS) could be a treatment option for medication-resistant auditory hallucinations (AH), but so far results have been inconclusive, and large sample trials have been missing. This study used tDCS as a treatment method for these hallucinations in a double-blind, placebo-controlled study with a relatively large sample size. Methods: Fifty-four patients of several diagnostic categories with medication-resistant AH were randomized and treated during 10 sessions of 20 min each, with either 2 mA tDCS or placebo, administered on five consecutive days (i.e., two sessions per day). Anodal stimulation was targeted at the left dorsolateral prefrontal cortex, cathodal stimulation at the left temporoparietal junction. AH severity was assessed using the Auditory Hallucination Rating Scale (AHRS). Other outcome measures were assessed with the Positive and Negative Syndrome Scale (PANSS), the Stroop, and the Trail Making Test. Results: AH frequency and severity decreased significantly over time, as did the scores on the total and general subscales of the PANSS. However, there was no significant interaction effect with the treatment group on any of the main outcome measures. Conclusions: We found no evidence that tDCS is more effective for medication-resistant AH than placebo, even though AH frequency and severity decreased in both groups. An alternative strategy may be to offer tDCS at an earlier stage of illness. In the light of recent investigations into the neurophysiological mechanisms behind tDCS, we may also have to consider the possibility that tDCS is not able to induce any long-lasting brain changes

Physical exercise improves quality of life, depressive symptoms, and cognition across chronic brain disorders: a transdiagnostic systematic review and meta-analysis of randomized controlled trials

We performed a meta-analysis to synthesize evidence on the efficacy and safety of physical exercise as an add-on therapeutic intervention for quality of life (QoL), depressive symptoms and cognition across six chronic brain disorders: Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Parkinson’s disease, schizophrenia and unipolar depression. 122 studies (= k) (n = 7231) were included. Exercise was superior to treatment as usual in improving QoL (k = 64, n = 4334, ES = 0.40, p < 0.0001), depressive symptoms (k = 60, n = 2909, ES = 0.78, p < 0.0001), the cognitive domains attention and working memory (k = 21, n = 1313, ES = 0.24, p < 0.009), executive functioning (k = 14, n = 977, ES = 0.15, p = 0.013), memory (k = 12, n = 994, ES = 0.12, p = 0.038) and psychomotor speed (k = 16, n = 896, ES = 0.23, p = 0.003). Meta-regression showed a dose–response effect for exercise time (min/week) on depressive symptoms (β = 0.007, p = 0.012). 69% of the studies that reported on safety, found no complications. Exercise is an efficacious and safe add-on therapeutic intervention showing a medium-sized effect on QoL and a large effect on mood in patients with chronic brain disorders, with a positive dose–response correlation. Exercise also improved several cognitive domains with small but significant effects

Simvastatin augmentation for recent-onset psychotic disorder : A study protocol

Background: There is ample evidence that inflammatory processes play a role in the pathophysiology of schizophrenia. Randomized controlled trials have shown benefit of some (but not all) anti-inflammatory drugs on symptom severity. So far, these drugs have been given for a relatively short period. Simvastatin combines well-established vascular protection with reduction of the inflammatory status of the brain, thus offering an attractive potential to further improve treatment of schizophrenia and related disorders. Methods/design: We are currently undertaking a double-blind placebo-controlled trial, including 250 patients (18-50. years of age) whom are diagnosed with a schizophrenia spectrum disorder. Onset of their first psychosis should be no longer than three years ago. Patients are randomized 1:1 to either 40. mg simvastatin or placebo daily during one year, next to their regular antipsychotic treatment. Primary outcome measures are symptom severity and cognitive decline as measured by the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS), at baseline and end of treatment. Secondary aims are to establish an attenuation of brain tissue loss and an improvement in general functioning, presence and severity of metabolic syndrome and degree of movement disorders. Lastly, immunological and metabolic parameters are assessed in blood samples to possibly predict treatment response. Discussion: We hypothesize simvastatin to lower symptom severity and to prevent or reduce excessive brain tissue loss and cognitive decline, compared to placebo. We expect that simvastatin will be well-tolerated and lead to decreased prevalence of metabolic syndrome. Trial registration: ClinicalTrails.gov NCT01999309; EudraCT-number 2013-000834-36