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    Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial. Koops Sanne,van Dellen Edwin,Schutte Maya J L,Nieuwdorp Wendy,Neggers Sebastiaan F W,Sommer Iris E C Schizophrenia bulletin BACKGROUND:Auditory verbal hallucinations (AVH) in schizophrenia are resistant to antipsychotic medication in approximately 25% of patients. Treatment with repetitive transcranial magnetic stimulation (rTMS) for refractory AVH has shown varying results. A stimulation protocol using continuous theta burst rTMS (TB-rTMS) showed high efficacy in open label studies. We tested TB-rTMS as a treatment strategy for refractory AVH in a double-blind, placebo-controlled trial. METHODS:Seventy-one patients with AVH were randomly allocated to TB-rTMS or placebo treatment. They received 10 TB-rTMS or sham treatments over the left temporoparietal cortex in consecutive days. AVH severity was assessed at baseline, end of treatment and follow-up using the Psychotic Symptom Rating Scale (PSYRATS) and the Auditory Hallucinations Rating Scale (AHRS). Other schizophrenia-related symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS:Seven patients dropped out before completing the study. In the remaining 64, AVH improved significantly after treatment in both groups as measured with both PSYRATS and AHRS. PANSS positive and general subscores also decreased, but the negative subscores did not. However, improvement did not differ significantly between the TB-rTMS and the placebo group on any outcome measure. CONCLUSIONS:Symptom reduction could be achieved in patients with medication-resistant hallucinations, even within 1 week time. However, as both groups showed similar improvement, effects were general (ie, placebo-effects) rather than specific to treatment with continuous TB-rTMS. Our findings highlight the importance of double-blind trials including a sham-control condition to assess efficacy of new treatments such as TMS. 10.1093/schbul/sbv100
    Effect of Bilateral Prefrontal rTMS on Left Prefrontal NAA and Glx Levels in Schizophrenia Patients with Predominant Negative Symptoms: An Exploratory Study. Dlabac-de Lange Jozarni J,Liemburg Edith J,Bais Leonie,van de Poel-Mustafayeva Aida T,de Lange-de Klerk Elly S M,Knegtering Henderikus,Aleman André Brain stimulation BACKGROUND:Prefrontal repetitive Transcranial Magnetic Stimulation (rTMS) may improve negative symptoms in patients with schizophrenia, but few studies have investigated the underlying neural mechanism. OBJECTIVE:This study aims to investigate changes in the levels of glutamate and glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate (NAA) in the left dorsolateral prefrontal cortex of patients with schizophrenia treated with active bilateral prefrontal rTMS as compared to sham-rTMS, as measured with H-Magnetic Resonance Spectroscopy (H-MRS). METHODS:Patients were randomized to a 3-week course of active or sham high-frequency rTMS. Pre-treatment and post-treatment H-MRS data were available for 24 patients with schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale ≥ 15). Absolute metabolite concentrations were calculated using LCModel with the water peak as reference. To explore the association between treatment condition and changes in concentration of Glx and NAA, we applied a linear regression model. RESULTS:We observed an increase of Glx concentration in the active treatment group and a decrease of Glx concentration in the group receiving sham treatment. The association between changes in Glx concentration and treatment condition was significant. No significant associations between changes in NAA and treatment condition were found. CONCLUSIONS:Noninvasive neurostimulation with high-frequency bilateral prefrontal rTMS may influence Glx concentration in the prefrontal cortex of patients with schizophrenia. Larger studies are needed to confirm these findings and further elucidate the underlying neural working mechanism of rTMS. 10.1016/j.brs.2016.08.002
    The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: A randomized rater blind-sham controlled study. Garg Shobit,Sinha Vinod Kumar,Tikka Sai Krishna,Mishra Preeti,Goyal Nishant Psychiatry research Repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic for schizophrenia. Treatment effects of rTMS have been variable across different symptom clusters, with negative symptoms showing better response, followed by auditory hallucinations. Cerebellum, especially vermis and its abnormalities (both structural and functional) have been implicated in cognitive, affective and positive symptoms of schizophrenia. rTMS to this alternate site has been suggested as a novel target for treating patients with this disorder. Hypothesizing cerebellar vermal magnetic stimulation as an adjunct to treat schizophrenia psychopathology, we conducted a double blind randomized sham controlled rTMS study. In this study, forty patients were randomly allocated (using block randomization method) to active high frequency (theta patterned) rTMS (n=20) and sham (n=20) groups. They received 10 sessions over 2 weeks. The Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) scores were assessed at baseline, after last session and at 4 weeks (2 weeks post-rTMS). We found a significantly greater improvement in the group receiving active rTMS sessions, compared to the sham group on negative symptoms, and depressive symptoms. We conclude that cerebellar stimulation can be used as an effective adjunct to treat negative and affective symptoms. 10.1016/j.psychres.2016.07.023
    Delayed effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia: Findings from a randomized controlled trial. Li Zhe,Yin Ming,Lyu Xiao-Li,Zhang Lan-Lan,Du Xiang-Dong,Hung Galen Chin-Lun Psychiatry research Evidence is inconsistent regarding the effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia. In this study, 47 patients were randomized to receive either active rTMS over left dorsolateral prefrontal cortex (n=25) or sham stimulation (n=22). Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) at baseline, 4 weeks and 8 weeks. At 4 weeks, there was no difference in SANS scores between 2 groups. By 8 weeks, patients with active rTMS had significantly reduced SANS score than controls. Our findings suggest a delayed effect of rTMS on negative symptoms. 10.1016/j.psychres.2016.04.046
    High-Frequency Neuronavigated rTMS in Auditory Verbal Hallucinations: A Pilot Double-Blind Controlled Study in Patients With Schizophrenia. Dollfus Sonia,Jaafari Nemat,Guillin Olivier,Trojak Benoit,Plaze Marion,Saba Ghassen,Nauczyciel Cécilia,Montagne Larmurier Aurélie,Chastan Nathalie,Meille Vincent,Krebs Marie-Odile,Ayache Samar S,Lefaucheur Jean Pascal,Razafimandimby Annick,Leroux Elise,Morello Rémy,Marie Batail Jean,Brazo Perrine,Lafay Nicolas,Wassouf Issa,Harika-Germaneau Ghina,Guillevin Remy,Guillevin Carole,Gerardin Emmanuel,Rotharmel Maud,Crépon Benoit,Gaillard Raphael,Delmas Christophe,Fouldrin Gael,Laurent Guillaume,Nathou Clément,Etard Olivier Schizophrenia bulletin INTRODUCTION:Despite extensive testing, the efficacy of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of temporo-parietal targets for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia is still controversial, but promising results have been reported with both high-frequency and neuronavigated rTMS. Here, we report a double-blind sham-controlled study to assess the efficacy of high-frequency (20 Hz) rTMS applied over a precise anatomical site in the left temporal region using neuronavigation. METHODS:Fifty-nine of 74 randomized patients with schizophrenia or schizoaffective disorders (DSM-IV R) were treated with rTMS or sham treatment and fully evaluated over 4 weeks. The rTMS target was determined by morphological MRI at the crossing between the projection of the ascending branch of the left lateral sulcus and the superior temporal sulcus (STS). RESULTS:The primary outcome was response to treatment, defined as a 30% decrease of the Auditory Hallucinations Rating Scale (AHRS) frequency item, observed at 2 successive evaluations. While there was no difference in primary outcome between the treatment groups, the percentages of patients showing a decrease of more than 30% of AHRS score (secondary outcome) did differ between the active (34.6%) and sham groups (9.1%) (P = .016) at day 14. DISCUSSION:This controlled study reports negative results on the primary outcome but demonstrates a transient effect of 20 Hz rTMS guided by neuronavigation and targeted on an accurate anatomical site for the treatment of AVHs in schizophrenia patients. 10.1093/schbul/sbx127
    Changes in motor cortical excitability in schizophrenia following transcranial direct current stimulation. Gordon Pedro Caldana,Valiengo Leandro da Costa Lane,de Paula Vanessa Jesus Rodrigues,Galhardoni Ricardo,Ziemann Ulf,de Andrade Daniel Ciampi,Brunoni Andre Russowsky Progress in neuro-psychopharmacology & biological psychiatry Schizophrenia is a disorder associated with cortical inhibition deficits. Transcranial direct current stimulation (tDCS) induces changes in cortical excitability in healthy subjects and individuals with neuropsychiatric disorders depending on the stimulation parameters. Our aim was to investigate whether a previously published tDCS protocol associated with symptomatic improvement in schizophrenia would induce changes in motor cortical excitability, assessed by transcranial magnetic stimulation paradigms, i.e., short-interval intracortical inhibition (SICI) and intra-cortical facilitation (ICF). We assessed cortical excitability measurements in 48 subjects with schizophrenia before and after a single session of active tDCS (20 min, 2 mA, anode over left dorsolateral prefrontal cortex, cathode over left temporoparietal cortex) or sham. Those who received active tDCS had a significant increase of SICI in the left motor cortex compared to those who received sham stimulation (Cohen's d = 0.54, p = .019). No changes were observed for ICF. In addition, lower SICI was associated with higher age (β = -0.448, p < .01). Increase in intracortical inhibition may indicate a mechanism of action of tDCS in this population. Future studies should investigate whether this finding is a biomarker of treatment response for schizophrenia. 10.1016/j.pnpbp.2018.11.004
    Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial. Hasan Alkomiet,Guse Birgit,Cordes Joachim,Wölwer Wolfgang,Winterer Georg,Gaebel Wolfgang,Langguth Berthold,Landgrebe Michael,Eichhammer Peter,Frank Elmar,Hajak Göran,Ohmann Christian,Verde Pablo E,Rietschel Marcella,Ahmed Raees,Honer William G,Malchow Berend,Karch Susanne,Schneider-Axmann Thomas,Falkai Peter,Wobrock Thomas Schizophrenia bulletin Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation. 10.1093/schbul/sbv142
    Prefrontal Transcranial Direct Current Stimulation for Treatment of Schizophrenia With Predominant Negative Symptoms: A Double-Blind, Sham-Controlled Proof-of-Concept Study. Palm Ulrich,Keeser Daniel,Hasan Alkomiet,Kupka Michael J,Blautzik Janusch,Sarubin Nina,Kaymakanova Filipa,Unger Ina,Falkai Peter,Meindl Thomas,Ertl-Wagner Birgit,Padberg Frank Schizophrenia bulletin Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (-36.1%) than after sham tDCS (-0.7%). PANSS sum scores decreased significantly more with active (-23.4%) than with sham stimulation (-2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia. 10.1093/schbul/sbw041
    Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis. Koutsouleris Nikolaos,Wobrock Thomas,Guse Birgit,Langguth Berthold,Landgrebe Michael,Eichhammer Peter,Frank Elmar,Cordes Joachim,Wölwer Wolfgang,Musso Francesco,Winterer Georg,Gaebel Wolfgang,Hajak Göran,Ohmann Christian,Verde Pablo E,Rietschel Marcella,Ahmed Raees,Honer William G,Dwyer Dominic,Ghaseminejad Farhad,Dechent Peter,Malchow Berend,Kreuzer Peter M,Poeppl Tim B,Schneider-Axmann Thomas,Falkai Peter,Hasan Alkomiet Schizophrenia bulletin Background:The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS. Methods:We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results:Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions:Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions. 10.1093/schbul/sbx114
    Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis. Hansbauer Maximilian,Wobrock Thomas,Kunze Birgit,Langguth Berthold,Landgrebe Michael,Eichhammer Peter,Frank Elmar,Cordes Joachim,Wölwer Wolfgang,Winterer Georg,Gaebel Wolfgang,Hajak Göran,Ohmann Christian,Verde Pablo E,Rietschel Marcella,Ahmed Raees,Honer William G,Malchow Berend,Strube Wolfgang,Schneider-Axmann Thomas,Falkai Peter,Hasan Alkomiet Psychiatry research Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS. 10.1016/j.psychres.2018.02.030
    Dissecting the syndrome of schizophrenia: Associations between symptomatology and hormone levels in women with schizophrenia. Thomas Natalie,Gurvich Caroline,Hudaib Abdul-Rahman,Gavrilidis Emorfia,Kulkarni Jayashri Psychiatry research Despite many studies implicating reproductive hormones in the development and outcome of schizophrenia, few have characterised the association between symptomatology and hormonal trajectories. To understand the influence of hormones on schizophrenia symptoms, serum steroids (estradiol, progesterone, follicular stimulating hormone (FSH), luteinising hormone (LH), and dehydroepiandrosterone (DHEA)) and psychopathology (The positive-and-negative-syndrome-scale(PANSS)) and depression (Montgomery-Asberg-Depression-Rating Scale(MADRS)) were collected across 12-weeks in 45 women (mean age 46) diagnosed with schizophrenia. To account for potential heterogeneity, Group-based-trajectory-modelling of psychopathology was used to identify distinct subgroups of individuals following a similar pattern of association between symptom score and hormone levels over-time. Two trajectories were identified for PANSS: one subgroup with lower symptom severity was associated with FSH, DHEA, LH, and another high severity subgroup associated with LH. Two trajectories were identified for MADRS: 'depressed' (associated with FSH), and non-depressed. The result delineates subpopulations with unique psychopathology and hormone associations that support the hypothesis that reproductive hormones play a role in the pathophysiology of schizophrenia, and that heterogeneity may exist in hormonal sensitivities in the schizophrenia population. Stratification of subjects according to biological phenotype may help improve existing treatments through personalised-medicine strategies. The endocrine system may be one such biological mechanism to continue dissecting the syndrome. 10.1016/j.psychres.2019.112510
    Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial. Brown Hannah E,Freudenreich Oliver,Fan Xiaoduo,Heard Stephen O,Goff Donald,Petrides George,Harrington Amy L,Kane John M,Judge Heidi,Hoeppner Bettina,Fava Maurizio,Perlis Roy H JAMA psychiatry Importance:Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia. Objective:To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance. Design, Setting, and Participants:Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used. Interventions:Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. Main Outcomes and Measures:Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase. Results:Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = -1.04; z = -0.59; P = .57), PANSS-positive (weighted β = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted β = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. Conclusions and Relevance:Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance. Trial Registration:ClinicalTrials.gov identifier: NCT02164981. 10.1001/jamapsychiatry.2019.0151
    Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study Kelly Deanna L.,Demyanovich Haley K.,Rodriguez Katrina M.,Ciháková Daniela,Talor Monica V.,McMahon Robert P.,Richardson Charles M.,Vyas Gopal,Adams Heather A.,August Sharon M.,Fasano Alessio,Cascella Nicola G.,Feldman Stephanie M.,Liu Fang,Sayer MacKenzie A.,Powell Megan M.,Wehring Heidi J.,Buchanan Robert W.,Gold James M.,Carpenter William T.,Eaton William W. Journal of psychiatry & neuroscience : JPN Background:Approximately one-third of people with schizophrenia have elevated levels of anti-gliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. Methods:In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and endpoint. Results:Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = –0.75) and in negative symptoms (Cohen d = –0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the glutencontaining group. Adverse effects were similar between groups. Limitations:This study was limited by its small sample size; larger studies are needed. Conclusion:This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder.
    A pilot study of bright light therapy in schizophrenia. Roopram Sheetal Madhvi,Burger Andreas Michael,van Dijk Dyllis Aimée,Enterman John,Haffmans Judith Psychiatry research Negative symptoms and episodes of major depressive disorder in patients with schizophrenia are common and there is an overlap in symptoms. Unfortunately, there is no effective primary treatment for negative symptoms yet. Depressive disorder in patients with schizophrenia is associated with a decreased quality of life and an increased risk of psychotic relapses. Previous research has shown that Bright Light Therapy (BLT) has a positive impact on negative symptoms of patients with schizophrenia. Our aim was to investigate the feasibility and the effect of Bright Light Therapy in a severely ill population of patients who were admitted to a closed ward. This pilot study was a single center, open label add-on trial with two control groups and included 20 patients. RESULTS:Neither negative nor positive symptoms were affected. However, there was a trend towards increase on the general psychopathology scale of the Positive And Negative Syndrome Scale in the BLT group. BLT did not change daily mood ratings. One participant from the BLT group was withdrawn from the study due to a manic state possibly triggered by BLT. Patients participating in our study did not benefit from BLT. It was an additional burden on the participants and worsened general psychopathology at a follow-up. Based on this study, we did not find any beneficial effect of BLT for patients with schizophrenia. 10.1016/j.psychres.2016.07.034
    Effects of bilateral prefrontal rTMS on brain activation during social-emotional evaluation in schizophrenia: A double-blind, randomized, exploratory study. Liemburg Edith J,Dlabac-De Lange Jozarni J,Bais Leonie,Knegtering Henderikus,Aleman André Schizophrenia research This exploratory study reports on the effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on (prefrontal) brain activity changes during ambiguous emotional evaluation in patients with schizophrenia. Before and after randomly assigned treatment with active and sham rTMS, patients performed the Wall of Faces task during fMRI scanning. fMRI analysis showed that rTMS treatment resulted in reduced activation of striato-fronto-parietal brain areas, while activation increased compared to baseline after sham. Thus, prefrontal rTMS may normalize an increased brain response to ambiguous emotional stimuli, but future studies should confirm these findings. 10.1016/j.schres.2018.06.051
    Intranasal oxytocin increases facial expressivity, but not ratings of trustworthiness, in patients with schizophrenia and healthy controls. Woolley J D,Chuang B,Fussell C,Scherer S,Biagianti B,Fulford D,Mathalon D H,Vinogradov S Psychological medicine BACKGROUND:Blunted facial affect is a common negative symptom of schizophrenia. Additionally, assessing the trustworthiness of faces is a social cognitive ability that is impaired in schizophrenia. Currently available pharmacological agents are ineffective at improving either of these symptoms, despite their clinical significance. The hypothalamic neuropeptide oxytocin has multiple prosocial effects when administered intranasally to healthy individuals and shows promise in decreasing negative symptoms and enhancing social cognition in schizophrenia. Although two small studies have investigated oxytocin's effects on ratings of facial trustworthiness in schizophrenia, its effects on facial expressivity have not been investigated in any population. METHOD:We investigated the effects of oxytocin on facial emotional expressivity while participants performed a facial trustworthiness rating task in 33 individuals with schizophrenia and 35 age-matched healthy controls using a double-blind, placebo-controlled, cross-over design. Participants rated the trustworthiness of presented faces interspersed with emotionally evocative photographs while being video-recorded. Participants' facial expressivity in these videos was quantified by blind raters using a well-validated manualized approach (i.e. the Facial Expression Coding System; FACES). RESULTS:While oxytocin administration did not affect ratings of facial trustworthiness, it significantly increased facial expressivity in individuals with schizophrenia (Z = -2.33, p = 0.02) and at trend level in healthy controls (Z = -1.87, p = 0.06). CONCLUSIONS:These results demonstrate that oxytocin administration can increase facial expressivity in response to emotional stimuli and suggest that oxytocin may have the potential to serve as a treatment for blunted facial affect in schizophrenia. 10.1017/S0033291716003433
    A Network Approach to Psychosis: Pathways Between Childhood Trauma and Psychotic Symptoms. Isvoranu Adela-Maria,van Borkulo Claudia D,Boyette Lindy-Lou,Wigman Johanna T W,Vinkers Christiaan H,Borsboom Denny, Schizophrenia bulletin Childhood trauma (CT) has been identified as a potential risk factor for the onset of psychotic disorders. However, to date, there is limited consensus with respect to which symptoms may ensue after exposure to trauma in early life, and whether specific pathways may account for these associations. The aim of the present study was to use the novel network approach to investigate how different types of traumatic childhood experiences relate to specific symptoms of psychotic disorders and to identify pathways that may be involved in the relationship between CT and psychosis. We used data of patients diagnosed with a psychotic disorder (n = 552) from the longitudinal observational study Genetic Risk and Outcome of Psychosis Project and included the 5 scales of the Childhood Trauma Questionnaire-Short Form and all original symptom dimensions of the Positive and Negative Syndrome Scale. Our results show that all 5 types of CT and positive and negative symptoms of psychosis are connected through symptoms of general psychopathology. These findings are in line with the theory of an affective pathway to psychosis after exposure to CT, with anxiety as a main connective component, but they also point to several additional connective paths between trauma and psychosis: eg, through poor impulse control (connecting abuse to grandiosity, excitement, and hostility) and motor retardation (connecting neglect to most negative symptoms). The results of the current study suggest that multiple paths may exist between trauma and psychosis and may also be useful in mapping potential transdiagnostic processes. 10.1093/schbul/sbw055
    Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. McGuire Philip,Robson Philip,Cubala Wieslaw Jerzy,Vasile Daniel,Morrison Paul Dugald,Barron Rachel,Taylor Adam,Wright Stephen The American journal of psychiatry OBJECTIVE:Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia. METHOD:In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S). RESULTS:After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups. CONCLUSIONS:These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder. 10.1176/appi.ajp.2017.17030325
    The brief negative symptom scale (BNSS): Sensitivity to treatment effects. Kirkpatrick Brian,Saoud Jay B,Strauss Gregory P,Ahmed Anthony O,Tatsumi Kazunori,Opler Mark,Luthringer Remy,Davidson Michael Schizophrenia research The Brief Negative Symptom Scale (BNSS) grew out of a recommendation by the NIMH-sponsored Consensus Development Conference on Negative Symptoms that a scale based on contemporary concepts be developed. We assessed sensitivity to change of the BNSS in a trial of MIN-101, which showed efficacy for negative symptoms (PANSS pentagonal model) at daily doses of 32 and 64mg/day. Using mixed-effects model for repeated measures, we examined change in BNSS total score and in the BNSS factors of anhedonia/avolition/asociality (AAA), and expressivity (EXP). Compared to placebo, the 64mg group (N=83) showed a significant decrease in BNSS total score (effect size d [ES] 0.56, p<0.01) and both factor scores (AAA ES=0.48, EXP ES=0.46, p<0.02 for both). Patients in the trial had minimal depression and positive symptom scores; covarying for disorganization, positive symptoms, or anxiety/depression did not cause a meaningful change in the significance of the BNSS total or factor scores in this group. The 32mg group (N=78) did not differ significantly from placebo (N=83) on BNSS total score (ES=0.33, p<0.09), AAA (ES=0.25, p<0.20) or EXP (ES=0.30, p<0.12) scores. These results demonstrate the BNSS is sensitive to change. 10.1016/j.schres.2017.11.031
    Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Morrison Anthony P,Pyle Melissa,Gumley Andrew,Schwannauer Matthias,Turkington Douglas,MacLennan Graeme,Norrie John,Hudson Jemma,Bowe Samantha E,French Paul,Byrne Rory,Syrett Suzy,Dudley Robert,McLeod Hamish J,Griffiths Helen,Barnes Thomas R E,Davies Linda,Kingdon David, The lancet. Psychiatry BACKGROUND:Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. METHODS:We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual. FINDINGS:From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event. INTERPRETATION:At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. FUNDING:National Institute for Health Research Technology Assessment programme. 10.1016/S2215-0366(18)30184-6
    Cognitive-behavioural therapy for clozapine-resistant schizophrenia: the FOCUS RCT. Morrison Anthony P,Pyle Melissa,Gumley Andrew,Schwannauer Matthias,Turkington Douglas,MacLennan Graeme,Norrie John,Hudson Jemma,Bowe Samantha,French Paul,Hutton Paul,Byrne Rory,Syrett Suzy,Dudley Robert,McLeod Hamish J,Griffiths Helen,Barnes Thomas Re,Davies Linda,Shields Gemma,Buck Deborah,Tully Sarah,Kingdon David Health technology assessment (Winchester, England) BACKGROUND:Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population. OBJECTIVES:To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome. DESIGN:The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU). SETTING:Secondary care mental health services in five cities in the UK. PARTICIPANTS:People with CRS aged ≥ 16 years, with an , Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms. INTERVENTIONS:Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services. MAIN OUTCOME MEASURES:The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs. RESULTS:Participants were allocated to CBT ( = 242) or TAU ( = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) -3.32 to 1.55 points;  = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (-2.40 points, 95% CI -4.79 to -0.02 points;  = 0.049). CBT was associated with a net cost of £5378 (95% CI -£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46;  = 0.58). CONCLUSIONS:Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained. TRIAL REGISTRATION:Current Controlled Trials ISRCTN99672552. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 7. See the NIHR Journals Library website for further project information. 10.3310/hta23070
    Predicting real-world functioning in outpatients with schizophrenia: Role of inflammation and psychopathology. Gonzalez-Blanco Leticia,Garcia-Portilla Maria Paz,Dal Santo Francesco,Garcia-Alvarez Leticia,de la Fuente-Tomas Lorena,Menendez-Miranda Isabel,Bobes-Bascaran Teresa,Saiz Pilar A,Bobes Julio Psychiatry research Several studies indicate that negative and cognitive symptoms are determining factors of functioning in patients with schizophrenia. However, they do not usually include biological aspects, such as inflammatory markers. The current prospective study aims to identify clinical and biological factors predicting real-world functioning, at baseline and at one-year follow-up, of outpatients in an early stage of schizophrenia. Sample consist of 73 clinically stable patients with schizophrenia, of which 57 completed the one-year follow-up. Accurate psychopathology, functioning, and cognitive assessments were performed at baseline and follow-up (Positive and Negative Syndrome, Brief Negative Symptom, Calgary Depression, Personal and Social Performance Scales, and MATRICS Cognitive Consensus Battery). Biological biomarkers including anthropometric data and blood parameters were collected. Pearson correlation and multiple regression analyses including potential confounding factors were performed. Negative symptoms (especially asociality and avolition), along with the inflammatory biomarker interleukin-2, are the most important determining factors of poor real-world functioning in early-stage schizophrenia. The previous functioning, along with baseline cognitive performance in attention and vigilance, predicts functioning at one-year follow-up in these patients. Strategies aimed at improving negative and cognitive symptoms, as well as modifying certain inflammatory pathways, should be the targets to achieve functional recovery in the first years of schizophrenia. 10.1016/j.psychres.2019.112509
    Clinical evaluation of functional capacity in treatment resistant schizophrenia patients: Comparison and differences with non-resistant schizophrenia patients. Iasevoli Felice,D'Ambrosio Luigi,Notar Francesco Danilo,Razzino Eugenio,Buonaguro Elisabetta Filomena,Giordano Sara,Patterson Thomas L,de Bartolomeis Andrea Schizophrenia research Treatment resistant schizophrenia (TRS) is defined by poor or non-response to conventional antipsychotic agents. Functional capacity is defined as the baseline potential of a patient to function in the community, irrespective of actual achievements gained, and has never been studied in TRS. Here, we screened 182 patients with psychotic symptoms and separated them in TRS (n = 28) and non-TRS (n = 32) ones, to evaluate whether they exhibited differential extents and predictive clinical variables of functional capacity. Functional capacity was measured by the UCSD Performance-Based Skills Assessment (UPSA). Psychotic symptoms by PANSS, social functioning by PSP and SLOF, clinical severity of the illness, cognitive functioning, and neurological soft signs (NSS) were assessed. TRS patients had non-significant lower UPSA scores compared to non-TRS (t-test: p > 0.05). In TRS, UPSA score correlated with multiple clinical variables. The highest effect sizes were observed for PANSS negative score (r = -0.67, p < 0.005); SLOF Area1 score (r = 0.66, p < 0.005); NSS severity (r = -0.61, p < 0.005). Multivariate analysis showed that main predictors of UPSA score in TRS patients were PANSS negative score, education years, NSS, Problem Solving performances, and PSP score (F = 11.12, R = 0.75, p < 0.0005). These variables were not predictive of UPSA score in non-TRS patients. Hierarchical analysis found that variance in UPSA score mainly depended on negative symptoms, NSS, and problem solving (F = 15.21, R = 0.65, p < 0.0005). Path analysis individuated two separate paths to UPSA score. These results delineate a limited and independent group of candidate predictors to be putatively accounted for therapeutic interventions to improve functional capacity, and possibly social functioning, in TRS patients. 10.1016/j.schres.2018.06.030
    Improving Pleasure and Motivation in Schizophrenia: A Randomized Controlled Clinical Trial. Favrod Jérôme,Nguyen Alexandra,Chaix Joséphine,Pellet Joanie,Frobert Laurent,Fankhauser Caroline,Ismailaj Alban,Brana Armando,Tamic Gwennaïg,Suter Caroline,Rexhaj Shyhrete,Golay Philippe,Bonsack Charles Psychotherapy and psychosomatics BACKGROUND:Negative symptoms are frequent in patients with schizophrenia and are associated with marked impairments in social functioning. The efficacy of drug-based treatments and psychological interventions on primary negative symptoms remains limited. The Positive Emotions Programme for Schizophrenia (PEPS) is designed to improve pleasure and motivation in schizophrenia patients by targeting emotion regulation and cognitive skills relevant to apathy and anhedonia. The main hypothesis of this study is that patients who attend 8 one-hour sessions of PEPS and treatment as usual (TAU) will have lower total apathy-avolition and anhedonia-asociality composite scores on the Scale for the Assessment of Negative Symptoms (SANS) than patients who attend only TAU. METHODS:Eighty participants diagnosed with schizophrenia or schizoaffective disorder were randomized to receive either TAU or PEPS + TAU. The participants were assessed by independent evaluators before randomization (T0), in a post-test after 8 weeks of treatment (T1) and at a 6-month follow-up (T2). RESULTS:The post-test results and 6-month follow-up assessments according to an intention-to-treat analysis showed that the apathy and anhedonia composite scores on the SANS indicated statistically greater clinical improvements in PEPS participants than in non-PEPS participants. In the post-test, anhedonia but not apathy was significantly improved, thus favouring the PEPS condition. These results were sustained at the 6-month follow-up. CONCLUSIONS:PEPS is an effective intervention to reduce anhedonia in schizophrenia. PEPS is a short, easy-to-use, group-based, freely available intervention that is easy to implement in a variety of environments (ClinicalTrials.gov ID: NCT02593058). 10.1159/000496479
    A randomized controlled trial of mindfulness in patients with schizophrenia. Lee Kun-Hua Psychiatry research Cognitive Behavioral Therapy (CBT) is frequently used to attenuate the severity of positive schizophrenia symptoms; however, few studies have focused on attenuating negative symptoms. Recently, researchers have become interested in the effects of mindfulness-based intervention (MBI) on schizophrenia, but the lack of evidence-based results from random clinical trials (RCTs) has limited their effectiveness. Moreover, longitudinal data must be examined using appropriate study designs. We recruited 60 schizophrenia patients and randomly assigned them to an MBI or to a treatment-as-usual group. Negative symptoms, positive symptoms, mindfulness, and depression were assessed at baseline, post-course, and at a 3-month follow-up. Descriptive analysis and generalized estimating equations (GEEs) were used to examine the effects of MBI. We found that MBI mitigated the severity of negative symptoms and of general schizophrenic psychopathology except for the positive symptoms and for those of depression. Unexpectedly, we did not find long-term effect of mindfulness on negative symptoms. Larger sample sizes, long-term practical course, more rigorous study procedures, and a double-blind design should be considered in future studies. 10.1016/j.psychres.2019.02.079
    Left prefrontal high-frequency rTMS may improve movement disorder in schizophrenia patients with predominant negative symptoms - A secondary analysis of a sham-controlled, randomized multicenter trial. Kamp Daniel,Engelke Christina,Wobrock Thomas,Wölwer Wolfgang,Winterer Georg,Schmidt-Kraepelin Christian,Gaebel Wolfgang,Langguth Berthold,Landgrebe Michael,Eichhammer Peter,Frank Elmar,Hajak Göran,Ohmann Christian,Verde Pablo E,Rietschel Marcella,Raees Ahmed,Honer William G,Malchow Berend,Schneider-Axmann Thomas,Falkai Peter,Hasan Alkomiet,Cordes Joachim Schizophrenia research 10.1016/j.schres.2018.09.017
    Suicidal Ideation in People With Psychosis Not Taking Antipsychotic Medication: Do Negative Appraisals and Negative Metacognitive Beliefs Mediate the Effect of Symptoms? Hutton Paul,Di Rienzo Francesca,Turkington Douglas,Spencer Helen,Taylor Peter Schizophrenia bulletin Between 5% and 10% of people with psychosis will die by suicide, a rate which is 20-75 times higher than the general population. This risk is even greater in those not taking antipsychotic medication. We examined whether negative appraisals of psychotic experiences and negative metacognitive beliefs about losing mental control mediated a relationship between psychotic symptoms and suicidal ideation in this group. Participants were diagnosed with schizophrenia spectrum disorders, antipsychotic-free for 6 months at baseline, and were participating in an 18-month randomized controlled trial of cognitive therapy vs treatment as usual. We conducted a series of mediation analyses with bootstrapping on baseline (N = 68), follow-up data (9-18 mo; n = 49), and longitudinal data (n = 47). Concurrent general symptoms were directly associated with suicidal ideation at baseline, and concurrent negative symptoms were directly associated with suicidal ideation at 9-18 months. Concurrent positive, negative, general, and overall symptoms were each indirectly associated with suicidal ideation via negative appraisals and/or negative metacognitive beliefs, at baseline and 9-18 months, except for negative symptoms at baseline. Controlling for baseline suicidal ideation and treatment allocation, baseline general symptoms were indirectly associated with later suicidal ideation, via baseline negative appraisals and negative metacognitive beliefs. Baseline negative metacognitive beliefs also had a direct association with later suicidal ideation. These findings suggest the clinical assessment of suicidal ideation in psychosis may be enhanced by considering metacognitive beliefs about the probability and consequences of losing mental control. 10.1093/schbul/sby153
    Associations between clinical and psychosocial factors and metabolic and cardiovascular risk factors in overweight patients with schizophrenia spectrum disorders - Baseline and two-years findings from the CHANGE trial. Storch Jakobsen Ane,Speyer Helene,Nørgaard Hans Christian Brix,Hjorthøj Carsten,Krogh Jesper,Mors Ole,Nordentoft Merete Schizophrenia research OBJECTIVES:People with severe mental disorders die averagely 15years earlier than people in the Western background population, cardiovascular disease being the most frequent cause of death with unhealthy eating habits and lower levels of physical activity as major contributing risk factors. Understanding possible associations and predictors of the specific cardiovascular risk may permit more targeted and effective prevention. The aim of this study was to investigate the associations between clinical and psychosocial factors and several separate cardiovascular risk factors in a cohort of 428 persons with schizophrenia and abdominal obesity enrolled in the CHANGE trial. METHODS:We used data from baseline and two-year follow-up of 428 individuals with schizophrenia spectrum disorders and abdominal overweight enrolled in the CHANGE trial. By linear regressions we explored the relationships between clinical and psychosocial factors and established cardiovascular risk factors: Dependent variables were baseline and follow-up values of the following: VOmax, waist circumference, high density lipoprotein (HDL), systolic blood pressure and HbA1c. Independent variables were baseline values of the following: negative symptoms, positive symptoms, cognition, level of functioning, antipsychotic medication, duration of illness, employment situation and whether the participants had any friend. RESULTS:Negative symptoms were associated with most baseline- as well as two-years-outcome; negatively with cardiorespiratory fitness and with dietary quality and with HDL, and with increasing values of the variables waist circumference, BMI and HbA1c. Negative symptoms were seen also to predict poorer cardiorespiratory fitness and larger waist circumference, higher HbA1c and lower HDL at two year follow-up. Level of functioning and Cognitive function correlated positively with cardiorespiratory fitness and HDL, and correlated negatively with waist circumference and HbA1c. Both parameters also predicted a better fitness, higher HDL and lower HbA1c at two year follow-up. Isolating the antipsychotic drugs known to give the worst metabolic adverse effects (olanzapine, clozapine, quetiapine), the dosage was positively associated with cholesterol, but not with any other outcome. Psychotic symptoms and duration of illness were not significantly associated with any outcome. Employment of any kind was significantly associated with cardiorespiratory fitness and negatively associated with waist circumference, BMI and systolic blood pressure. At two year follow-up associations were significant for the two year outcomes cardiorespiratory fitness and waist circumference. Friendship relations were negatively associated with waist circumference and positively with HDL cholesterol. None of the two year outcomes were predicted by friendship. CONCLUSIONS:We found various clinical and psychosocial factors to be associated with less healthy lifestyle factors and higher risk of cardiovascular disease, with negative symptoms building the strongest associations, although a possible bidirectional causality needs to be regarded. Reduction of negative symptoms should be investigated further in order to reduce the increased cardiovascular morbidity and mortality in people with schizophrenia spectrum disorders. 10.1016/j.schres.2018.02.047
    The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Deakin Bill,Suckling John,Barnes Thomas R E,Byrne Kelly,Chaudhry Imran B,Dazzan Paola,Drake Richard J,Giordano Annalisa,Husain Nusrat,Jones Peter B,Joyce Eileen,Knox Emma,Krynicki Carl,Lawrie Stephen M,Lewis Shôn,Lisiecka-Ford Danuta M,Nikkheslat Naghmeh,Pariante Carmine M,Smallman Richard,Watson Andrew,Williams Steven C R,Upthegrove Rachel,Dunn Graham, The lancet. Psychiatry BACKGROUND:The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. METHODS:In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. FINDINGS:Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). INTERPRETATION:Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. FUNDING:National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership. 10.1016/S2215-0366(18)30345-6
    The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Fleischhacker Wolfgang,Galderisi Silvana,Laszlovszky István,Szatmári Balázs,Barabássy Ágota,Acsai Károly,Szalai Erzsébet,Harsányi Judit,Earley Willie,Patel Mehul,Németh György European psychiatry : the journal of the Association of European Psychiatrists BACKGROUND:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D-preferring D/D receptor partial agonist and serotonin 5-HT receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms. METHODS:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227). RESULTS:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P < .05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P < .01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P < .05). CONCLUSIONS:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia. 10.1016/j.eurpsy.2019.01.015
    Validation study of the Brief Medication Adherence Scale (BMAS) in patients with schizophrenia and related disorders in Hong Kong. Chui E,Wong K L,Chan K Y,Wong M Asian journal of psychiatry The purpose of this study was to develop and test an original self-rating instrument known as Brief Medication Adherence Scale (BMAS) to assess antipsychotic adherence level of Hong Kong Chinese patients with schizophrenia. On the interview day, BMAS and three other validated rating scales were given to local patients with schizophrenia and related disorders for completion. BMAS was required to fill in a second time after two weeks for the study of test-retest reliability. Results of BMAS were matched with those of other scales and blood level of prescribed mood stabilizers to test for construct validity. Data analysis was performed for 84 patients. Median BMAS scores recorded at both times were identical at 89/100, and a cutoff score of 70 was considered medication adherent with a sensitivity of 98.61% (CI 92.50%-99.96%). BMAS was positively and significantly correlated with the established Medication Adherence Rating Scale -Taiwanese (Spearman's ρ = 0.56, p < 0.05) and with variation in serum mood stabilizer level (Pearson's r = 0.55, p < 0.05). On the other hand, correlations with scales measuring mental condition and medication side effects were weak. Principal component analysis found two components (i.e. medication taking behaviors and attitudes) for the 10-question BMAS. Test-retest BMAS total scores were significantly correlated (intraclass correlation alpha = 0.87, p < 0.05), and Cronbach's alpha measuring internal consistency was 0.68. The current study confirms that BMAS is a valid and reliable scale that assesses medication adherence in patients with schizophrenia. 10.1016/j.ajp.2018.09.005